Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor

ABSTRACT

The present invention relates to Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.

This application claims the benefit of provisional application U.S. Ser.No. 60/684,726, filed May 26, 2005, which is hereby incorporated byreference into the subject application in its entirety.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art as known to those skilled therein as ofthe date of the invention described and claimed herein.

This patent disclosure contains material that is subject to copyrightprotection. The copyright owner has no objection to the facsimilereproduction by anyone of the patent document or the patent disclosure,as it appears in the U.S. Patent and Trademark Office patent file orrecords, but otherwise reserves any and all copyright rights whatsoever.

FIELD OF THE INVENTION

The present invention relates to Gonadotropin Releasing Hormone (GnRH,also known as Luteinizing Hormone Releasing Hormone) receptorantagonists.

BACKGROUND OF THE INVENTION

Gonadotropin Releasing Hormone is a decameric peptide released from thehypothalamus. In the anterior pituitary gland, GnRH activates the GnRHreceptor. Activation of the GnRH receptor triggers the release offollicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH andLH stimulate the biosynthesis and release of sex steroids in the gonadsof both genders.

Typically, this stimulation and release is desirable, but certainGnRH-related disorders exist where it would be beneficial to preventactivation of the GnRH receptor. For example, inhibition of the GnRHreceptor can lead to a large drop in sex steroid production, which inturn can alleviate sex hormone-related conditions such as prostatecancer, endometriosis, uterine fibroids, uterine cancer, breast cancer,ovarian cancer, testicular cancer, or primary hirsutism. Moreover, thereare other situations where it would be beneficial to prevent activationof the GnRH receptor, such as during some points of the in vitrofertilization process, for example, to prevent LH surge.

Currently marketed GnRH therapeutics are peptides that exhibit receptorantagonism in one of two ways. The first is through GnRH receptorsuperagonism. The GnRH receptor, when stimulated in bursts, causesnormal release of the gonadotropins, FSH and LH. Under constantstimulation, the receptor becomes desensitized and the overall effect isGnRH receptor inhibition. The superagonism process is undesirable,because inhibition via this process can take up to two weeks to have aneffect in human patients. During this delay, there is often an increasein disease symptoms due to the initial hormone stimulation phase. Thisphenomenon is referred to as flare.

The second method for receptor inhibition is through direct antagonismof the GnRH receptor with peptide antagonists. This causes an immediatedrop in plasma LH levels. However, as mentioned above, currentpharmaceuticals that cause blockade of the GnRH receptor are allpeptides. As such they are not orally bioavailable and must beadministered via parenteral means such as intravenous, subcutaneous, orintramuscular injection. Thus, an orally effective GnRH antagonist wouldbe of great benefit.

The present invention is directed to these and other important ends.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides compounds of the formula (I):

-   and pharmaceutically acceptable salts thereof,-   wherein-   X is N or C—R₂₈;-   Y is Q and Z is R₁₈; or Y is R₁₈ and Z is Q, wherein Q is

-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ are each    independently hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or    —CON(R₁₃)(R₁₄);-   X₁ is —O—, —NR₁₂—, or —SO_(m)—;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In another embodiment, the invention provides compounds of the formula(II):

and pharmaceutically acceptable salts thereof, wherein each of R₆, Y,and Z are as described above for compounds of the formula (I).

In another embodiment, the compounds or pharmaceutically acceptablesalts of the compounds of Formula (I) or Formula (II) are useful aspharmaceutical compositions comprising compounds or pharmaceuticallyacceptable salts of compounds of Formula (I) or Formula (II) and apharmaceutically acceptable carrier.

In one embodiment, the compounds or pharmaceutically acceptable salts ofthe compounds of the Formula (I) or Formula (II) are useful as GnRHreceptor antagonists.

In one embodiment, the invention provides methods for treating aGnRH-related disorder, comprising administering to a mammal in needthereof the compounds or pharmaceutically acceptable salts of compoundsof Formula (I) or Formula (II) in an amount effective to treat aGnRH-related disorder. In another embodiment, the invention providesmethods for preventing pregnancy, comprising administering to a femalemammal the compounds or pharmaceutically acceptable salts of compoundsof the Formula (I) or Formula (II) in an amount effective to preventpregnancy.

In one embodiment, the invention provides methods of synthesizing thecompounds or pharmaceutically acceptable salts of compounds of Formula(I) or Formula (II). In another embodiment, the invention providescompounds or pharmaceutically acceptable salts of compounds of Formula(I) or Formula (II) made by particular processes.

DESCRIPTION OF THE INVENTION

Definitions

The term “(C₁-C₆)-alkyl” as used herein refers to a linear or branched,saturated hydrocarbon having from 1 to 6 carbon atoms, Representative(C₁-C₆)-alkyl groups include, but are not limited to, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, and neohexyl. In one embodiment, the(C₁-C₆)-alkyl group is substituted with one or more of the followinggroups: halogen, —N₃, —NO₂, —CN, —OR′, —SR′, —SO₂R′, —SO₂N(R′)₂,—N(R′)₂, —COR′, —CO₂R′, —NR′CO₂R′, —NR′COR′, —NR′CONR′, or —CON(R′)₂,wherein each R′ is independently hydrogen or unsubstituted(C₁-C₆)-alkyl.

The term “(C₂-C₆)-alkenyl” as used herein refers to a linear or branchedhydrocarbon having from 2 to 6 carbon atoms and having at least onecarbon-carbon double bond. In one embodiment, the (C₂-C₆)-alkenyl hasone or two double bonds. The (C₂-C₆)-alkenyl moiety may exist in the Eor Z conformation and the compounds of the present invention includeboth conformations. In one embodiment, the (C₂-C₆)-alkenyl group issubstituted with one or more of the following groups: halogen, —N₃,—NO₂, —CN, —OR′, —SR′, —SO₂R′, —SO₂N(R′)₂, —N(R′)₂, —COR′, —CO₂R′,—NR′CO₂R′, —NR′COR-, —NR′CONR′, or —CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl.

The term “(C₂-C₆)-alkynyl” as used herein refers to a linear or branchedhydrocarbon having from 2 to 6 carbon atoms and having at least onecarbon-carbon triple bond. In one embodiment, the (C₂-C₆)-alkenyl groupis substituted with one or more of the following groups: halogen, —N₃,—NO₂, —CN, —OR′, —SR′, —SO₂R′, —SO₂N(R′)₂, —N(R′)₂, —COR′, —CO₂R′,—NR′CO₂R′, —NR′COR′, —NR′CONR′, or —CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl.

The term “administer”, “administering”, or “administration”, as usedherein refers to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to ananimal, or administering a prodrug derivative or analog of the compoundor pharmaceutically acceptable salt of the compound or composition tothe animal, which can form an equivalent amount of active compoundwithin the animal's body.

The term “animal” as used herein includes, without limitation, a human,mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee,baboon, or rhesus. In one embodiment, the animal is a mammal. In anotherembodiment, the animal is a human.

The term “amine protecting group” as used herein refers to a moiety thattemporarily blocks an amine reactive site in a compound. Generally, thisis done so that a chemical reaction can be carried out at anotherreactive site in a multifunctional compound or to otherwise stabilizethe amine. In one embodiment, an amine protecting group is selectivelyremovable by a chemical reaction. An exemplary amine protecting group isa carbamate protecting group. Carbamate protecting groups include,without limitation, t-butyl carbamate, methyl carbamate, ethylcarbamate, 2,2,2-trichloroethyl carbamate, 2-(trimethylsilyl)ethylcarbamate, 1,1-dimethyl-2,2,2-trichloroethyl carbamate, benzylcarbamate, p-methoxybenzyl carbamate, p-nitrobenzylcarbamate,p-bromobenzyl carbamate, p-chlorobenzyl carbamate, and2,4-dichlorobenzyl carbamate. See, Greene and Wuts, Protecting Groups inOrganic Synthesis, Second Edition, John Wiley & Sons (1991).

The term “aryl” as used herein refers to an aromatic species containing1 to 3 aromatic rings, either fused or linked. In one embodiment, thearyl group is substituted with one or more of the following groups:(C₁-C₆)-alkyl, —V-halogen, —V—N₃, —V—NO₂, —V—CN, —V—OR′, —V—SR′,—V—SO₂R′, —V—SO₂N(R′)₂, —V—N(R′)₂, —V—COR′, —V—CO₂R′, —V—NR′CO₂R′,—V—NR′COR′, —V—NR′CONR′, or —V—CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl; and wherein eachV is independently a bond or (C₁-C₆)-alkyl.

The term “conditions effective to” as used herein refers to syntheticreaction conditions which will be apparent to those skilled in the artof synthetic organic chemistry.

The term “cyclic group” as used herein includes a cycloalkyl group and aheterocyclic group. Any suitable ring position of the cyclic group maybe covalently linked to the defined chemical structure. In oneembodiment, the cyclic group is substituted with one or more of thefollowing groups: (C₁-C₆)-alkyl, —V-halogen, —V—N₃, —V—NO₂, —V—CN,—V—OR′, —V—SR′, —V—SO₂R′, —V—SO₂N(R′)₂, —V—N(R′)₂, —V—COR′, —V—CO₂R′,—V—NR′CO₂R′, —V—NR′COR′, —V—NR′CONR′, or —V—CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl; and wherein eachV is independently a bond or (C₁-C₆)-alkyl.

The term “cycloalkyl group” as used herein refers to a three- toseven-membered saturated or partially unsaturated carbon ring. Anysuitable ring position of the cycloalkyl group may be covalently linkedto the defined chemical structure. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Inone embodiment, the cycloalkyl group is substituted with one or more ofthe following groups: (C₁-C₆)-alkyl, —V-halogen, —V—N₃, —V—NO₂, —V—CN,—V—OR′, —V—SR′, —V—SO₂R′, —V—SO₂N(R′)₂, —V—N(R′)₂, —V—COR′, —V—CO₂R′,—V—NR′CO₂R′, —V—NR′COR′, —V—NR′CONR′, or —V—CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl; and wherein eachV is independently a bond or (C₁-C₆)-alkyl.

The term “effective amount” as used herein refers to an amount of acompound or pharmaceutically acceptable salt of a compound that, whenadministered to an animal, is effective to prevent, to at leastpartially ameliorate, or to cure, a condition from which the animalsuffers or is suspected to suffer.

The term “FSH” as used herein refers to follicle stimulating hormone.

The term “GnRH” as used herein refers to Gonadotropin Releasing Hormone.

The term “Gonadotropin Releasing Hormone-related disorder” or“GnRH-related disorder” as used herein refers to a condition for whichit would be beneficial to prevent activation of the GnRH receptor.Exemplary GnRH-related disorders include, without limitation, sexhormone-related conditions, sex hormone-dependent cancers, prostatecancer, testicular cancer, uterine cancer, ovarian cancer, breastcancer, pituitary gonadotrophe adenomas, endometriosis, polycysticovarian disease, uterine fibroids, primary hirsutism, luteinizinghormone surge, and precocious puberty.

The term “LH” as used herein refers to luteinizing hormone.

The term “halogen” as used herein refers to fluorine, chlorine, bromine,and iodine.

The term “heterocyclic group” as used herein refers to a three- toseven-membered saturated, partially saturated, or unsaturated cycloalkylgroup in which one to four of the ring carbon atoms have beenindependently replaced with a N, O, or S atom. Any suitable ringposition of the heterocyclic group may be covalently linked to thedefined chemical structure. Exemplary heterocyclic groups include, butare not limited to, azepanyl, azetidinyl, aziridinyl, furanyl,furazanyl, homopiperazinyl, imidazolidinyl, imidazolinyl, isothiazolyl,isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl,oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiomorpholinyl,thiophenyl, triazinyl, and triazolyl. In one embodiment, theheterocyclic group is substituted with one or more of the followinggroups: (C₁-C₆)-alkyl, —V-halogen, —V—N₃, —V—NO₂, —V—CN, —V—OR′, —V—SR′,—V—SO₂R′, —V—SO₂N(R′)₂, —V—N(R′)₂, —V—COR′, —V—CO₂R′, —V—NR′CO₂R′,—V—NR′COR′, —V—NR′CONR′, or —V—CON(R′)₂, wherein each R′ isindependently hydrogen or unsubstituted (C₁-C₆)-alkyl; and wherein eachV is independently a bond or (C₁-C₆)-alkyl.

The term “isolated and purified” as used herein refers to an isolatethat is separate from other components of a reaction mixture or anatural source. In certain embodiments, the isolate contains at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, or at least about 98%of the compound or pharmaceutically acceptable salt of the compound byweight of the isolate.

The term “pharmaceutically acceptable salt” as used herein refers to asalt of an acid and a basic nitrogen atom of a compound of the presentinvention. Exemplary salts include, but are not limited to, sulfate,citrate, acetate, oxalate, chloride, hydrochloride, bromide,hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, camphorsulfonate,napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate,mandelate, malate, phthalate, and pamoate. The term “pharmaceuticallyacceptable salt” as used herein also refers to a salt of a compound ofthe present invention having an acidic functional group, such as acarboxylic acid functional group, and a base. Exemplary bases include,but are not limited to, hydroxide of alkali metals including sodium,potassium, and lithium; hydroxides of alkaline earth metals such ascalcium and magnesium; hydroxides of other metals, such as aluminum andzinc; ammonia, organic amines such as unsubstituted orhydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like. Theterm “pharmaceutically acceptable salt” also includes a hydrate of acompound of the present invention.

The term “phenyl” as used herein refers to a substituted orunsubstituted phenyl group. In one embodiment, the phenyl group issubstituted with one or more of the following groups: (C₁-C₆)-alkyl,—V-halogen, —V—N₃, —V—NO₂, —V—CN, —V—OR′, —V—SR′, —V—SO₂R′,—V—SO₂N(R′)₂, —V—N(R′)₂, —V—COR′, —V—CO₂R′, —V—NR′CO₂R′, —V—NR′COR′,—V—NR′CONR′, or —V—CON(R′)₂, wherein each R′ is independently hydrogenor unsubstituted (C₁-C₆)-alkyl; and wherein each V is independently abond or (C₁-C₆)-alkyl.

The term “substantially free of its corresponding opposite enantiomer”as used herein means that the compound contains no more than about 10%by weight of its corresponding opposite enantiomer. In otherembodiments, the compound that is substantially free of itscorresponding opposite entantiomer contains no more than about 5%, nomore than about 1%, no more than about 0.5%, or no more than about 0.1%by weight of its corresponding opposite enantiomer. An enantiomer thatis substantially free of its corresponding opposite enantiomer includesa compound that has been isolated and purified or has been preparedsubstantially free of its corresponding opposite enantiomer.

The term “tautomer” as used herein refers to compounds produced by thephenomenon wherein a proton of one atom of a molecule shifts to anotheratom. See, Jerry March, Advanced Organic Chemistry: Reactions,Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages69-74 (1992).

The following abbreviations as used herein mean: Ac is acetate; boc ist-butyl carbamate; Bu is butyl; dba is dibenzylideneacetone; DCE is1,2-dichloroethane; DCM is dichloromethane; DIEA isdiisopropylethylamine; DMF is dimethylformamide; DMSO isdimethylsulfoxide; ESI is electrospray ionization; Et is ethyl; HPLC ishigh pressure liquid chromatography; HRMS is high resolution massspectrometry; LCMS is liquid chromatograph-mass spectrometry; Me ismethyl; MS is mass spectrometry; m/z is mass-to-charge ratio; NMP isN-methyl pyrrolidine; NMR is nuclear magnetic resonance; r.t. isretention time; TFA is trifluoroacetic acid; THF is tetrahydrofuran.

Compounds and Pharmaceutically Acceptable Salts of Compounds of theInvention

The compounds or pharmaceutically acceptable salts of compounds of thepresent invention can contain an asymmetric carbon atom and some of thecompounds or pharmaceutically acceptable salts of compounds of theinvention can contain one or more asymmetric centers, and can thus giverise to optical isomers and diastereomers. While depicted withoutrespect to stereochemistry in the compounds or pharmaceuticallyacceptable salts of compounds of the present invention, the presentinvention includes such optical isomers and diastereomers, as well asracemic and resolved, enantiomerically pure R and S stereoisomers, andalso other mixtures of the R and S stereoisomers and pharmaceuticallyacceptable salts thereof. Where a stereoisomer is provided, it can insome embodiments be provided substantially free of its correspondingopposite enantiomer.

In addition, the compounds and pharmaceutically acceptable salts ofcompounds of the present invention can exist as tautomers. Suchtautomers can be transient or isolatable as a stable product. Thesetautomers are within the scope of the present invention.

Prodrugs of the compounds or pharmaceutically acceptable salts ofcompounds are also within the scope of the present invention.

Compounds of the Formula (I)

In one embodiment, the present invention is directed to compounds of theFormula (I):

-   and pharmaceutically acceptable salts thereof,-   wherein-   X is N or C—R₂₈;-   Y is Q and Z is R₁₈; or Y is R₁₈ and Z is Q, wherein Q is

-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ are each    independetly hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or    —CON(R₁₃)(R₁₄);-   X₁ is —O-, —NR₁₂-, or —SO_(m)-;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, Ar is phenyl.

In another embodiment, one R₆ substituent is attached at the 4 positionof phenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cycloalkyl group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃and R₁₄ are each independently linear or branched (C₁-C₆)-alkyl, eachoptionally substituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄may be taken together to form a three- to seven-membered heterocyclicgroup containing one or two heteroatoms selected from N or O, andoptionally substituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach independently hydrogen, or linear or branched (C₁-C₆)-alkyl.

In another embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen.

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach hydrogen; R₁, R₂, R₄, and R₅ are each independently hydrogen, orlinear or branched (C₁-C₆)-alkyl; Ar is phenyl; R₆ is attached at the4-position of phenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂,or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ areeach independently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, andR₂₇ are each hydrogen; R₁ and R₄ are each independently hydrogen,methyl, or ethyl; Ar is phenyl; R₆ is attached at the 4-position ofphenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

In one embodiment, the compound is6-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline;3-{4-[2-(4-tert-Butyl-phenyl)-imidazol[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-pyrido[2,3-b]pyrazine;2-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline;2-(4-tert-Butyl-phenyl)-5-[4-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine;5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione;5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione;5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione;5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione;2-(4-tert-Butyl-phenyl)-8-[4-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine;2-(4-tert-Butyl-phenyl)-8-[4-(1-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine;6-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline;2-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline;or2-{4-[2-(4-tert-Butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline.

Compounds of the Formula (IA)

In one embodiment, the invention is directed to compounds of the Formula(IA):

-   and pharmaceutically acceptable salts thereof,-   wherein-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ are each    independently hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or    —CON(R₁₃)(R₁₄);-   X₁ is —O-, —NR₁₂-, or —SO_(m)-;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, Ar is phenyl.

In another embodiment, one R₆ substituent is attached at the 4 positionof phenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cycloalkyl group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃and R₁₄ are each independently linear or branched (C₁-C₆)-alkyl, eachoptionally substituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄may be taken together to form a three- to seven-membered heterocyclicgroup containing one or two heteroatoms selected from N or O, andoptionally substituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach independently hydrogen, or linear or branched (C₁-C₆)-alkyl.

In another embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen.

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach hydrogen; R₁, R₂, R₄, and R₅ are each independently hydrogen, orlinear or branched (C₁-C₆)-alkyl; Ar is phenyl; R₆ is attached at the4-position of phenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂,or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ areeach independently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, andR₂₇ are each hydrogen; R₁ and R₄ are each independently hydrogen,methyl, or ethyl; Ar is phenyl; R₆ is attached at the 4-position ofphenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

Compounds of the Formula (IB)

In one embodiment, the invention is directed to compounds of the Formula(IB):

-   and pharmaceutically acceptable salts thereof,-   wherein-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇, and R₂₈ are each    independently hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or -COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(n)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or    —CON(R₁₃)(R₁₄);-   X₁ is —O—, —NR₁₂—, or —SO_(m)—;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, Ar is phenyl.

In another embodiment, one R₆ substituent is attached at the 4 positionof phenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cycloalkyl group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃and R₁₄ are each independently linear or branched (C₁-C₆)-alkyl, eachoptionally substituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄may be taken together to form a three- to seven-membered heterocyclicgroup containing one or two heteroatoms selected from N or O, andoptionally substituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach independently hydrogen, or linear or branched (C₁-C₆)-alkyl.

In another embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen.

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach hydrogen; R₁, R₂, R₄, and R₅ are each independently hydrogen, orlinear or branched (C₁-C₆)-alkyl; Ar is phenyl; R₆ is attached at the4-position of phenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂,or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ areeach independently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, andR₂₇ are each hydrogen; R₁ and R₄ are each independently hydrogen,methyl, or ethyl; Ar is phenyl; R₆ is attached at the 4-position ofphenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

Compounds of the Formula (IC)

In one embodiment, the invention is directed to compounds of the Formula(IC):

-   and pharmaceutically acceptable salts thereof,-   wherein-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, 'NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇ are each    independently hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃,    —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or    —CON(R₁₃)(R₁₄);-   X₁ is —O-, —NR₁₂-, or —SO_(m)-;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, Ar is phenyl.

In another embodiment, one R₆ substituent is attached at the 4 positionof phenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cycloalkyl group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃and R₁₄ are each independently linear or branched (C₁-C₆)-alkyl, eachoptionally substituted with CR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ maybe taken together to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach independently hydrogen, or linear or branched (C₁-C₆)-alkyl.

In another embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen.

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach hydrogen; R₁, R₂, R₄, and R₅ are each independently hydrogen, orlinear or branched (C₁-C₆)-alkyl; Ar is phenyl; R₆ is attached at the4-position of phenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂,or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ areeach independently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, andR₂₇ are each hydrogen; R₁ and R₄ are each independently hydrogen,methyl, or ethyl; Ar is phenyl; R₆ is attached at the 4-position ofphenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

Compounds of the Formula (ID)

In one embodiment, the invention is directed to compounds of the Formula(ID):

-   and pharmaceutically acceptable salts thereof,-   wherein-   Ar is phenyl, 2-thiophenyl or 3-thiophenyl;-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇ are each    independently hydrogen; or linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each    optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,    —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,    —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;    —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃or    —CON(R₁₃)(R₁₄);-   X₁ is —O-, —NR₁₂-, or —SO_(m)-;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, Ar is phenyl.

In another embodiment, one R₆ substituent is attached at the 4 positionof phenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cycloalkyl group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or

-   NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃ and R₁₄    are each independently linear or branched (C₁-C₆)-alkyl, each    optionally substituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and    R₁₄ may be taken together to form a three- to seven-membered    heterocyclic group containing one or two heteroatoms selected from N    or O, and optionally substituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or    —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach independently hydrogen, or linear or branched (C₁-C₆)-alkyl.

In another embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen.

In one embodiment, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ areeach hydrogen; R₁, R₂, R₄, and R₅ are each independently hydrogen, orlinear or branched (C₁-C₆)-alkyl; Ar is phenyl; R₆ is attached at the4-position of phenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂,or —NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ areindependently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, andR₂₇ are each hydrogen; R₁ and R₄ are each independently hydrogen,methyl, or ethyl; Ar is phenyl; R₆ is attached at the 4-position ofphenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

Compounds of the Formula (II)

In another embodiment, the invention provides compounds of the Formula(II):

-   and pharmaceutically acceptable salts thereof,-   wherein-   Y is Q and Z is hydrogen; or Y is hydrogen and Z is Q, wherein Q is

-   R₁ and R₂ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a    three- to seven-membered cycloalkyl group, wherein the cycloalkyl    group formed by R₁ and R₂ is optionally substituted with halogen,    —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,    —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₃ is one of the following:

-   each R₃ also having up to three R₁₀ substituents attached to the    ring of R₃ containing at least one N;-   R₄, R₅, R₁₀, and R₂₃ are each independently hydrogen; or linear or    branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;-   each R₆ is independently hydrogen; linear or branched (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted    with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃;    or —COR₁₃; and when two R₆ are ortho to each other, they may    together form a five- to seven-membered cyclic group containing up    to 3 heteroatoms selected from N, O, or S, and wherein the cyclic    group formed by the ortho R₆ groups is optionally substituted with    halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂,    —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂,    —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;-   R₇ and R₉ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂;    —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂;-   R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,    or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂;-   R₁₁ and R₁₂ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂    may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₃ and R₁₄ are each independently hydrogen; linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally    substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,    —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,    —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted    with one to three substituents selected from halogen, R₁₅, —OR₁₅, or    —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to    seven-membered heterocyclic group containing up to 3 heteroatoms    selected from N, O, or S, and wherein the heterocyclic group formed    by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,    —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,    —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or    —(CH₂)_(n)OR₂₃;-   R₁₅ and R₁₆ are each independently hydrogen; or linear or branched    (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and    R₁₆ may together form a three- to seven-membered heterocyclic group    containing up to 3 heteroatoms selected from N, O, or S;-   R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;-   X₁ is —O-, —NR₁₂-, or —SO_(m)-;-   each m is independently 0, 1, or 2; and-   each n is independently 0, 1, 2, 3, or 4.

In one embodiment, one R₆ substituent is attached at the 4 position ofphenyl.

In one embodiment, R₁ and R₂ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl; or R₁ and R₂ may together form a three- toseven-membered cyclic group.

In another embodiment, R₁ and R₂ are hydrogen.

In one embodiment, R₁ is linear or branched (C₁-C₆)-alkyl and R₂ ishydrogen.

In one embodiment, R₁ is methyl and R₂ is hydrogen.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound.

In one embodiment, R₄ and R₅ are each independently hydrogen, or linearor branched (C₁-C₆)-alkyl.

In one embodiment, R₄ and R₅ are hydrogen.

In another embodiment, R₄ is linear or branched (C₁-C₆)-alkyl and R₅ ishydrogen.

In one embodiment, R₄ is methyl or ethyl and R₅ is hydrogen.

In another embodiment, when R₄ is other than hydrogen, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₄ is bound.

In one embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the S-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In another embodiment, when R₁ and R₂ are different, the compound orpharmaceutically acceptable salt of the compound is the R-enantiomerwith respect to the carbon to which R₁ and R₂ are bound, and when R₄ isother than hydrogen, the compound or pharmaceutically acceptable salt ofthe compound is the S-enantiomer with respect to the carbon to which R₄is bound.

In one embodiment, R₆ is hydrogen, linear or branched (C₁-C₆)-alkyl,—N(R₂₃)₂, or

-   NR₁₃R₁₄; R₂₃ is linear or branched (C₁-C₆)-alkyl; and R₁₃ and R₁₄    are each independently linear or branched (C₁-C₆)-alkyl, each    optionally substituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and    R₁₄ may be taken together to form a three- to seven-membered    heterocyclic group containing one or two heteroatoms selected from N    or O, and optionally substituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or    —(CH₂)_(n)OR₂₃.

In one embodiment, R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl.

In one embodiment, R₃ is

In another embodiment, R₃ is

In one embodiment, R₁, R₂, R₄, and R₅ are each independently hydrogen,or linear or branched (C₁-C₆)-alkyl; R₆ is attached at the 4-position ofphenyl; R₆ is linear or branched (C₁-C₆)-alkyl, —N(R₂₃)₂, or —NR₁₃R₁₄;R₂₃ is linear or branched (C₁-C₆)-alkyl; R₁₃ and R₁₄ are eachindependently linear or branched (C₁-C₆)-alkyl, each optionallysubstituted with —OR₂₃, —SR₂₃, or —N(R₂₃)₂; or R₁₃ and R₁₄ may be takentogether to form a three- to seven-membered heterocyclic groupcontaining one or two heteroatoms selected from N or O, and optionallysubstituted with —OR₂₃, —SR₂₃, —N(R₂₃)₂, or —CH₂)_(n)OR₂₃; and R₃ is

In one embodiment, R₂, and R₅ are each hydrogen; R₁ and R₄ are eachindependently hydrogen, methyl, or ethyl; R₆ is attached at the4-position of phenyl; R₆ is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃ is

Methods for Making the Compounds and Pharmaceutically Acceptable Saltsof Compounds of the Invention

The compounds and pharmaceutically acceptable salts of compounds of thepresent invention can be prepared using a variety of methods startingfrom commercially available compounds, known compounds, or compoundsprepared by known methods. General synthetic routes to many of thecompounds of the invention are included in the following schemes. It isunderstood by those skilled in the art that protection and deprotectionsteps not shown in the Schemes may be required for these syntheses, andthat the order of steps may be changed to accommodate functionality inthe target molecule.

Scheme 1 demonstrates the synthesis of a compound or pharmaceuticallyacceptable salt of a compound of the Formula (IA), wherein Ar, R₁, R₂,R₃, R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ areas defined above, and R₂₉ is Cl or Br. A compound of the Formula (III)is first reacted under conditions effective to bring about cyclization,thereby providing a compound having the Formula (IV). The compound ofFormula (IV) is then reacted with a piperazine, providing a compoundhaving the Formula (V). The free amine of the piperazine of Formula (V)is subsequently reacted under conditions effective to provide a compoundof the Formula (IA).

Scheme 2 provides the synthesis of a specific intermediate following thegeneral procedures set forth in Scheme 1, which can be furtherelaborated to provide compounds of the Formula (IA). The intermediate,2-(4-tert-butyl-phenyl)-8-piperazin-1-yl-imidazo[1,2-a]pyridine (1, wasprepared from either of two starting materials (Scheme 2).2-Amino-3-chloropyridine (1a) was prepared from 2,3-dichloropyridinefollowing a known method. 2-Amino-3-bromo pyridine (1b) is availablefrom commercial sources. The 2-amino-3-halo-pyridines (1a and 1b) werecyclized with 4-tert-butylphenacyl chloride to afford (1a and 1b).Intermediate (3) was obtained via a Buchwald reaction usingCbz-piperazine as the solvent with intermediate (2a). After purificationthe Cbz group was removed with catalytic hydrogenation, providing (4).Another approach was also employed using (2b). A Buchwald coupling withexcess piperazine afforded (4) directly.

Further elaboration of the intermediate (4), can include, for example,alkylation with 6-bromomethyl-quinoxaline heated in the presence of DIEAin a solvent such as acetonitrile, or reductive amination of anappropriate aldehyde in the presence of NaBH(OAc)₃ in a solvent such asNMP or DCE.

Scheme 3 demonstrates the synthesis of a compound or pharmaceuticallyacceptable salt of a compound of Formula (IB) wherein Ar, R₁, R₂, R₃,R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ are asdefined above. As shown in Scheme 3, an aminopyridine of the Formula(VI) is reacted under conditions effective to bring about cyclization,thereby providing a compound having the Formula (VII). Halogenating thecompound of the Formula (VII) and reacting with a piperazine provides acompound having the Formula (VIII). The free amine of the piperazine ofFormula (VIII) is subsequently reacted under conditions effective toprovide a compound of the Formula (IB).

Scheme 4 provides the synthesis of a specific intermediate following thegeneral procedures set forth in Scheme 3, which can be furtherelaborated to provide compounds of the Formula (IB).2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (7) wasobtained as described in Scheme 4. 2-Aminopyridine was cyclized with4-tert-butylphenacyl chloride to afford2-(4-tert-butyl-phenyl-imidazo[1,2-a]pyridine (5). Lithiation followedby bromination provided a ratio of three products (6a, 70.7%; 6b, 12.3%;and 6c, 17.0%). Heating the mixture with piperazine provided (7) from(6a), which was easily separated from unreactive (6b) and (6c).

Further elaboration of the intermediate (7), can include, for example,alkylation with 6-bromomethyl-quinoxaline heated in the presence of DIEAin a solvent such as acetonitrile, or reductive amination of anappropriate aldehyde in the presence of NaBH(OAc)₃ in a solvent such asNMP or DCE.

Scheme 5 demonstrates the synthesis of a compound or pharmaceuticallyacceptable salt of a compound of the Formula (IC), wherein Ar, R₁, R₂,R₃, R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are asdefined above. An aminopyridine of the Formula (VI) is reacted underconditions effective to provide a diaminopyridinium iodide having theFormula (IX). The compound of the Formula (IX) is then reacted underconditions effective to bring about cyclization, thereby providing acompound having the Formula (X). Halogenating the compound of theFormula (X) and reacting with a piperazine provides a compound havingthe Formula (XI). The free amine of the piperazine of Formula (XI) issubsequently reacted under conditions effective to provide a compound ofthe Formula (IC).

Scheme 6 provides the synthesis of a specific intermediate following thegeneral procedures set forth in Scheme 5, which can be furtherelaborated to provide compounds of the Formula (IC). As shown in Scheme6, 2-aminopyridine was converted to 1,2-diamino-pyridinium iodide (8).This was cyclized with 4-tert-butyl-benzoyl chloride, providing (9).Intermediate (9) was brominated and the product (10) was treated withpiperazine in DMSO while heating to provide2-(4-tert-butyl-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyridine(11).

Further elaboration of the intermediate (11), can include, for example,alkylation with 6-bromomethyl-quinoxaline heated in the presence of DIEAin a solvent such as acetonitrile, or reductive amination of anappropriate aldehyde in the presence of NaBH(OAc)₃ in a solvent such asNMP or DCE.

Scheme 7 shows the synthesis of a compound or pharmaceuticallyacceptable salt of a compound of the Formula (ID), wherein Ar, R₁, R₂,R₃, R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are asdefined above. A hydrazinonitropyridine of the Formula (XII) is reactedunder conditions effective to provide a compound of the Formula (XIII).The compound of Formula (XIII) is then under conditions effective tobring about isomerization to provide a compound of the Formula (XIV),Reducing the nitro group of the compound of Formula (XIV) provides acompound of the Formula (XV). Diazotizing and halogenating the compoundof Formula (XV) and reacting with piperazine provides a compound of theFormula (XVI). The free amine of the piperazine of Formula (XVI) issubsequently reacted under conditions effective to provide a compound ofthe Formula (ID).

Scheme 8 provides the synthesis of a specific intermediate following thegeneral procedures set forth in Scheme 7, which can be furtherelaborated to provide a compound of the Formula (ID). Scheme 8 outlinesa method for the preparation of the piperazine intermediate,2-(4-tert-butyl-phenyl)-8-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyridine(16). Following the literature protocol from Potts and Surapaneni(Journal of Heterocyclic Chemistry, 7:1019-1027 (1970)),2-hydrazino-3-nitropyridine is treated with 4-tert-butyl-benzoic acidwhile heating. Isomerization of intermediate product,3-(4-tert-Butyl-phenyl)-8-nitro-[1,2,4]triazolo[4,3-a]pyridine (12)during the reaction provides2-(4-tert-Butyl-phenyl)-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (13),Reduction of the nitro group provides (14). Subsequent diazotization andhalogenation gives the 8-halo products (15) following the procedures ofVan Heertum et. al. (U.S. Pat. No. 5,571,775 (1996)). Treatment withpiperazine using, for example, Buchwald conditions provides (6).

Further elaboration of the intermediate (16), can include, for example,alkylation with 6-bromomethyl-quinoxaline heated in the presence of DIEAin a solvent such as acetonitrile, or reductive amination of anappropriate aldehyde in the presence of NaBH(OAc)₃ in a solvent such asNMP or DCE.

One of skill in the art will recognize that Schemes 1-8 can be adaptedto produce the other compounds and pharmaceutically acceptable salts ofcompounds according to the present invention.

Therapeutic Administration

When administered to an animal, the compounds or pharmaceuticallyacceptable salts of the compounds of the invention can be administeredneat or as a component of a composition that comprises a physiologicallyacceptable carrier or vehicle. A composition of the invention can beprepared using a method comprising admixing the compound or apharmaceutically acceptable salt of the compound and a physiologicallyacceptable carrier, excipient, or diluent. Admixing can be accomplishedusing methods well known for admixing a compound or a pharmaceuticallyacceptable salt of the compound and a physiologically acceptablecarrier, exipient, or diluent.

The present compositions, comprising compounds or pharmaceuticallyacceptable salts of the compounds of the invention can be administeredorally. The compounds or pharmaceutically acceptable salts of compoundsof the invention can also be administered by any other convenient route,for example, by infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral, rectal, vaginal, andintestinal mucosa, etc.) and can be administered together with anothertherapeutic agent. Administration can be systemic or local. Variousknown delivery systems, including encapsulation in liposomes,microparticles, microcapsules, and capsules, can be used.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. In some instances, administration will result of release of thecompound or a pharmaceutically acceptable salt of the compound into thebloodstream. The mode of administration is left to the discretion of thepractitioner.

In one embodiment, the compound or a pharmaceutically acceptable salt ofthe compound is administered orally.

In another embodiment, the compound or a pharmaceutically acceptablesalt of the compound is administered intravenously.

In another embodiment, it may be desirable to administer the compound ora pharmaceutically acceptable salt of the compound locally. This can beachieved, for example, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository oredema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the compound ora pharmaceutically acceptable salt of the compound into the centralnervous system, circulatory system or gastrointestinal tract by anysuitable route, including intraventricular, intrathecal injection,paraspinal injection, epidural injection, enema, and by injectionadjacent to the peripheral nerve. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compound or a pharmaceutically acceptable saltof the compound can be formulated as a suppository, with traditionalbinders and excipients such as triglycerides.

In another embodiment, the compound or a pharmaceutically acceptablesalt of the compound can be delivered in a vesicle, in particular aliposome (see Langer, Science 249:1527-1533 (1990) and Treat et al.,Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and353-365 (1989)).

In yet another embodiment, the compound or a pharmaceutically acceptablesalt of the compound can be delivered in a controlled-release system orsustained-release system (see, e.g., Goodson, in Medical Applications ofControlled Release, vol. 2, pp. 115-138 (1984)). Other controlled orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit, Ref. Biomed.Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci, Rev. Macromol. Chem. 2:61 (1983); Levy etal., Science 228:190 (1935); During et al., Ann. Neural. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)).

In yet another embodiment, a controlled- or sustained-release system canbe placed in proximity of a target of the compound or a pharmaceuticallyacceptable salt of the compound, e.g., the reproductive organs, thusrequiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of aphysiologically acceptable excipient.

Such physiologically acceptable excipients can be liquids, such as waterand oils, including those of petroleum, animal, vegetable, or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil and thelike. The physiologically acceptable excipients can be saline, gumacacia, gelatin, starch paste, talc, keratin, colloidal silica, urea andthe like. In addition, auxiliary, stabilizing, thickening, lubricating,and coloring agents can be used. In one embodiment the physiologicallyacceptable excipients are sterile when administered to an animal. Thephysiologically acceptable excipient should be stable under theconditions of manufacture and storage and should be preserved againstthe contaminating action of microorganisms. Water is a particularlyuseful excipient when the compound or a pharmaceutically acceptable saltof the compound is administered intravenously. Saline solutions andaqueous dextrose and glycerol solutions can also be employed as liquidexcipients, particularly for injectable solutions. Suitablephysiologically acceptable excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups, and elixirs. The compound or pharmaceuticallyacceptable salt of the compound of this invention can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water,an organic solvent, a mixture of both, or pharmaceutically acceptableoils or fat. The liquid carrier can contain other suitablepharmaceutical additives including solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers, orosmo-regulators. Suitable examples of liquid carriers for oral andprenteral administration include water (particular containing additivesas above, e.g., cellulose derivatives, including sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule.Other examples of suitable physiologically acceptable excipients aredescribed in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R.Gennaro, ed., 19th ed. 1995).

In one embodiment, the compound or a pharmaceutically acceptable salt ofthe compound is formulated in accordance with routine procedures as acomposition adapted for oral administration to humans. Compositions fororal delivery can be in the form of tablets, lozenges, buccal forms,troches, aqueous or oily suspensions or solutions, granules, powders,emulsions, capsules, syrups, or elixirs for example. Orally administeredcompositions can contain one or more agents, for example, sweeteningagents such as fructose, aspartame or saccharin; flavoring agents suchas peppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.In powders, the carrier can be a finely divided solid, which is anadmixture with the finely divided compound or pharmaceuticallyacceptable salt of the compound. In tablets, the compound orpharmaceutically acceptable salt of the compound is mixed with a carrierhaving the necessary compression properties in suitable proportions andcompacted in the shape and size desired. The powders and tablets cancontain up to about 99% of the compound or pharmaceutically acceptablesalt of the compound.

Capsules may contain mixtures of the compounds or pharmaceuticallyacceptable salts of the compounds with inert fillers and/or diluentssuch as pharmaceutically acceptable starches (e.g., corn, potato, ortapioca starch), sugars, artificial sweetening agents, powderedcelluloses (such as crystalline and microcrystalline celluloses),flours, gelatins, gums, etc.

Tablet formulations can be made by conventional compression, wetgranulation, or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents (including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrroldine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents, Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine.

Moreover, when in a tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tract,thereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound or a pharmaceutically acceptable salt of the compoundare also suitable for orally administered compositions. In these latterplatforms, fluid from the environment surrounding the capsule can beimbibed by the driving compound, which swells to displace the agent oragent composition through an aperture. These delivery platforms canprovide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment the excipients are ofpharmaceutical grade.

In another embodiment, the compound or a pharmaceutically acceptablesalt of the compound can be formulated for intravenous administration.Typically, compositions for intravenous administration comprise sterileisotonic aqueous buffer. Where necessary, the compositions can alsoinclude a solubilizing agent. Compositions for intravenousadministration can optionally include a local anesthetic such aslignocaine to lessen pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water-freeconcentrate in a hermetically sealed container such as an ampule orsachette indicating the quantity of active agent. Where the compound ora pharmaceutically acceptable salt of the compound is to be administeredby infusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thecompound or a pharmaceutically acceptable salt of the compound isadministered by injection, an ampule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

In another embodiment, the compound or pharmaceutically acceptable saltof the compound can be administered transdermally thorugh the use of atransdermal patch. Transdermal administrations include administrationsacross the surface of the body and the inner linings of the bodilypassages including epithelial and mucosal tissues. Such administrationscan be carried out using the present compounds or pharmaceuticallyacceptable salts of the compounds, in lotions, creams, foams, patches,suspensions, solutions, and suppositories (e.g., rectal or vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing the compound or pharmaceutically acceptablesalt of the compound and a carrier that is inert to the compound orpharmaceutically acceptable salt of the compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams or ointments, pastes, gels, or occlusive devices. The creamsor ointments may be viscous liquid or semisolid emulsions of either theoil-in-water or water-in-oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the compound or pharmaceutically acceptable saltof the compound into the blood stream, such as a semi-permeable membranecovering a reservoir containing the compound or pharmaceuticallyacceptable salt of the compound with or without a carrier, or a matrixcontaining the active ingredient.

The compounds or pharmaceutically acceptable salts of the compounds ofthe invention may be administered rectally or vaginally in the form of aconventional suppository. Suppository formulations may be made fromtraditional materials, including cocoa butter, with or without theaddition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polyethylene glycolsof various molecular weights, may also be used.

The compound or a pharmaceutically acceptable salt of the compound canbe administered by controlled-release or sustained-release means or bydelivery devices that are known to those of ordinary skill in the art.Such dosage forms can be used to provide controlled- orsustained-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known to those skilled in the art,including those described herein, can be readily selected for use withthe active ingredients of the invention. The invention thus encompassessingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled- or sustained-release.

In one embodiment a controlled- or sustained-release compositioncomprises a minimal amount of the compound or a pharmaceuticallyacceptable salt of the compound to treat or prevent a GnRH-relateddisorder in a minimal amount of time. Advantages of controlled- orsustained-release compositions include extended activity of the drug,reduced dosage frequency, and increased compliance by the animal beingtreated. In addition, controlled- or sustained-release compositions canfavorably affect the time of onset of action or other characteristics,such as blood levels of the compound or a pharmaceutically acceptablesalt of the compound, and can thus reduce the occurrence of adverse sideeffects.

Controlled- or sustained-release compositions can initially release anamount of the compound or a pharmaceutically acceptable salt of thecompound that promptly produces the desired therapeutic or prophylacticeffect, and gradually and continually release other amounts of thecompound or a pharmaceutically acceptable salt of the compound tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the compound ora pharmaceutically acceptable salt of the compound in the body, thecompound or a pharmaceutically acceptable salt of the compound can bereleased from the dosage form at a rate that will replace the amount ofthe compound or a pharmaceutically acceptable salt of the compound beingmetabolized and excreted from the body. Controlled- or sustained-releaseof an active ingredient can be stimulated by various conditions,including but not limited to, changes in pH, changes in temperature,concentration or availability of enzymes, concentration or availabilityof water, or other physiological conditions or compounds.

In certain embodiments, the present invention is directed to prodrugs ofthe compounds or pharmaceutically acceptable salts of compounds of thepresent invention. Various forms of prodrugs are known in the art, forexample as discussed in Bundgaard (ed.), Design of Prodrugs, Elsevier(1985); Widder et al (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Kgrogsgaard-Larsen et al. (ed.); “Design and Applicationof Prodrugs”, Textbook of Drug Design and Development, Chapter 5,113-191 (1991); Bundgaard et al., Journal of Drug Delivery Reviews,8:1-38 (1992); Bundgaard et al., J. Pharmaceutical Sciences, 77:285 etseq. (1988); and Higuchi and Stella (eds.), Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975).

The amount of the compound or a pharmaceutically acceptable salt of thecompound is an amount that is effective for treating or preventing aGnRH-related disorder. In addition, in vitro or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed can also depend on the route ofadministration, the condition, the seriousness of the condition beingtreated, as well as various physical factors related to the individualbeing treated, and can be decided according to the judgment of ahealth-care practitioner. Equivalent dosages may be administered overvarious time periods including, but not limited to, about every 2 hours,about every 6 hours, about every 8 hours, about every 12 hours, aboutevery 24 hours, about every 36 hours, about every 48 hours, about every72 hours, about every week, about every two weeks, about every threeweeks, about every month, and about every two months. The number andfrequency of dosages corresponding to a completed course of therapy willbe determined according to the judgment of a health-care practitioner.The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one compound or a pharmaceuticallyacceptable salt of the compound is administered, the effective dosageamounts correspond to the total amount administered.

The amount of the compound or a pharmaceutically acceptable salt of thecompound that is effective for treating or preventing a GnRH-relateddisorder will typically range from about 0.001 mg/kg to about 250 mg/kgof body weight per day, in one embodiment, from about 1 mg/kg to about250 mg/kg body weight per day, in another embodiment, from about 1 mg/kgto about 50 mg/kg body weight per day, and in another embodiment, fromabout 1 mg/kg to about 20 mg/kg of body weight per day.

In one embodiment, the pharmaceutical composition is in unit dosageform, e.g., as a tablet, capsule, powder, solution, suspension,emulsion, granule, or suppository. In such form, the composition issub-divided in unit dose containing appropriate quantities of the activeingredient; the unit dosage form can be packaged compositions, forexample, packeted powders, vials, ampoules, prefilled syringes orsachets containing liquids. The unit dosage form can be, for example, acapsule or tablet itself, or it can be the appropriate number of anysuch compositions in package form. Such unit dosage form may containfrom about 1 mg/kg to about 250 mg/kg, and may be given in a single doseor in two or more divided doses.

The compound or a pharmaceutically acceptable salt of the compound canbe assayed in vitro or in vivo for the desired therapeutic orprophylactic activity prior to use in humans. Animal model systems canbe used to demonstrate safety and efficacy.

The present methods for treating or preventing a GnRH-related disorder,can further comprise administering another therapeutic agent to theanimal being administered the compound or a pharmaceutically acceptablesalt of the compound. In one embodiment the other therapeutic agent isadministered in an effective amount.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective amount range. The compound or a pharmaceutically acceptablesalt of the compound and the other therapeutic agent can act additivelyor, in one embodiment, synergistically. In one embodiment of theinvention, where another therapeutic agent is administered to an animal,the effective amount of the compound or a pharmaceutically acceptablesalt of the compound is less than its effective amount would be wherethe other therapeutic agent is not administered. In this case, withoutbeing bound by theory, it is believed that the compound or apharmaceutically acceptable salt of the compound and the othertherapeutic agent act synergistically.

In one embodiment, the other therapeutic agent is selected from thegroup consisting of at least one of androgens, estrogens, progesterones,antiestrogens, antiprogestogens, testosterone, angiotensin-convertingenzyme inhibitor (such as ENALPRIL or CAPTOPRIL), angiotensinII-receptor antagonist (such as LOSARTAN), renin inhibitor,bisphosphonates (bisphosphonic acids), growth hormone secretagogues(such as MK-0677), 5a-reductase 2 inhibitor (such as finasteride orepristeride) a 5a-reductase 1 inhibitor (such as4,7b-dimethyl-4-aza-5a-cholestan-3-one,3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a-androstane, and3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane), dual inhibitorsof 5a-reductase 1 and 5a-reductase 2 (such as3-oxo-4-aza-17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstan),antiandrogens (such as flutamide, casodex and cyproterone acetate),alpha-1 blockers (such as prazosin, terazosin, doxazosin, tamsulosin,and alfuzosin), growth hormone, and luteinizing hormone releasingcompounds (such as a peptide, including leuprorelin, gonadorelin,buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin,meterlin and recirelin, or a natural hormone or analog thereof).

For example, when used with compounds or pharmaceutically acceptablesalts of compounds of the present invention: androgens, estrogens,progesterones, antiestrogens and antiprogestogens find use in thetreatment of endometriosis, fibroids, and in contraception; testosteroneor other androgens or antiprogestogens find use in men as acontraceptive; angiotensin-converting enzyme inhibitors, angiotensinII-receptor antagonists, and renin inhibitor find use in the treatmentof uterine fibroids; bisphosphonates (bisphosphonic acids) and growthhormone secretagogues find use in the treatment and prevention ofdisturbances of calcium, phosphate and bone metabolism, in particular,for the prevention of bone loss during therapy with the GnRH antagonist,and in combination with estrogens, progesterones, antiestrogens,antiprogesterones and/or androgens for the prevention or treatment ofbones loss or hypogonadal symptoms such as hot flashes during therapywith the GnRH antagonist; and growth hormone, growth hormone releasinghormone or growth hormone secretagogues, to delay puberty in growthhormone deficient children. Additional therapeutic agents useful incombination with the compounds or pharmaceutically acceptable salts ofcompounds of the present invention include 5a-reductase 2 inhibitor,5a-reductase 1 inhibitor, dual inhibitors of 5a-reductase 1 and5a-reductase 2, antiandrogens, alpha-1 blockers, and compounds havingluteinizing hormone releasing activity.

In one embodiment, the compound or a pharmaceutically acceptable salt ofthe compound is administered concurrently with another therapeuticagent.

In one embodiment, a composition comprising an effective amount of thecompound or a pharmaceutically acceptable salt of the compound and aneffective amount of another therapeutic agent within the samecomposition can be administered.

In another embodiment, a composition comprising an effective amount ofthe compound or a pharmaceutically acceptable salt of the compound and aseparate composition comprising an effective amount of anothertherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of the compound or a pharmaceuticallyacceptable salt of the compound is administered prior to or subsequentto administration of an effective amount of another therapeutic agent.In this embodiment, the compound or a pharmaceutically acceptable saltof the compound is administered while the other therapeutic agent exertsits therapeutic effect, or the other therapeutic agent is administeredwhile the compound or a pharmaceutically acceptable salt of the compoundexerts its preventative or therapeutic effect for treating or preventinga GnRH-related disorder.

Thus, in one embodiment, the invention provides a composition comprisingan effective amount of the compound or a pharmaceutically acceptablesalt of the compound of the present invention and a pharmaceuticallyacceptable carrier.

In another embodiment, the composition further comprises a therapeuticagent selected from the group consisting of androgen, estrogen,progesterone, antiestrogen, antiprogestogen, testosterone,angiotensin-converting enzyme inhibitor, angiotensin II-receptorantagonist, renin inhibitor, bisphosphonate, growth hormonesecretagogue, 5a-reductase 2 inhibitor, a 5a-reductase 1 inhibitor, adual inhibitor of 5a-reductase 1 and 5a-reductase 2, antiandrogen,alpha-1 blockers, growth hormone, and luteinizing hormone releasingcompound; or a combination thereof.

In another embodiment, the pharmaceutically acceptable carrier issuitable for oral administration and the composition comprises an oraldosage form.

Therapeutic or Prophylactic Uses

In one embodiment, the compounds or pharmaceutically acceptable salts ofthe compounds of the present invention are useful as GnRH receptorantagonists. Accordingly, the compounds and pharmaceutically acceptablesalts of the compounds of the present invention are useful for treatinga mammal with a GnRH-related disorder.

In one embodiment, the invention provides a method for treating aGnRH-related disorder, comprising administering to a mammal in needthereof a compound or a pharmaceutically acceptable salt of the compoundof Formula (I) or Formula (II) in an amount effective to treat aGnRH-related disorder. In another embodiment, the compound orpharmaceutically acceptable salt of the compound is of the Formula (IA),(IB), (IC), or (ID).

In one embodiment, the GnRH-related disorder is a sex hormone-relatedcondition.

In one embodiment, the GnRH-related disorder is a sex hormone-dependentcancer. In another embodiment, the GnRH-related disorder is prostatecancer, testicular cancer, uterine cancer, ovarian cancer, breastcancer, or pituitary gonadotrophe adenomas. In one embodiment, theGnRH-related disorder is breast cancer.

In another embodiment, the GnRH-related disorder is endometriosis,polycystic ovarian disease, uterine fibroids, primary hirsutism,luteinizing hormone surge, or precocious puberty.

In another embodiment, the invention provides a method for preventingpregnancy, comprising administering to a female mammal the compound orpharmaceutically acceptable salt of the compound of Formula (I) orFormula (II) in an amount effective to prevent pregnancy. In anotherembodiment, the compound or pharmaceutically acceptable salt of thecompound is of the Formula (IA), (IB), (IC), or (ID).

In yet another embodiment, the methods of the present invention furthercomprise administering to the mammal a therapeutic agent selected fromthe group consisting of androgen, estrogen, progesterone, antiestrogen,antiprogestogen, testosterone, angiotensin-converting enzyme inhibitor,angiotensin II-receptor antagonist, renin inhibitor, bisphosphonate,growth hormone secretagogue, 5a-reductase 2 inhibitor, a 5a-reductase 1inhibitor, a dual inhibitor of 5a-reductase 1 and 5a-reductase 2,antiandrogen, alpha-1 blockers, growth hormone, and luteinizing hormonereleasing compound; or a combination thereof.

In one embodiment, the present invention is directed to a method formodulating the activity of a Gonadotropin Releasing Hormone receptor,comprising contacting the receptor with an effective amount of acompound or pharmaceutically acceptable salt of the compound of Formula(I) or Formula (II). In one embodiment, the method further comprisesdetermining the activity of the receptor. In one embodiment, the step ofdetermining the activity of the receptor is performed before the step ofcontacting the receptor with the compound or a pharmaceuticallyacceptable salt of the compound. In another embodiment, the step ofdetermining the activity of the receptor is performed after the step ofcontacting the receptor with the compound or a pharmaceuticallyacceptable salt of the compound. In another embodiment, the compound orpharmaceutically acceptable salt of the compound is of the Formula (IA),(IB), (IC), or (ID).

The compounds and pharmaceutically acceptable salts of the compounds ofFormula (I) or Formula (II) are also useful in the manufature ofmedicaments for treating a GnRH-related disorder in a mammal. In anotherembodiment, the compound or pharmaceutically acceptable salt of thecompound is of the Formula (IA), (IB), (IC), or (ID).

Accordingly, in one embodiment, the invention provides the use of acompound or pharmaceutically acceptable salt of the compound of Formula(I) or Formula (II) for the manufacture of a medicament for treating aGnRH-related disorder. In another embodiment, the compound orpharmaceutically acceptable salt of the compound is of the Formula (IA),(IB), (IC), or (ID).

In one embodiment, the GnRH-related disorder is a sex hormone-relatedcondition.

In one embodiment, the GnRH-related disorder is a sex hormone-dependentcancer. In another embodiment, the GnRH-related disorder is prostatecancer, testicular cancer, uterine cancer, ovarian cancer, breastcancer, or pituitary gonadotrophe adenomas. In one embodiment, theGnRH-related disorder is breast cancer.

In another embodiment, the GnRH-related disorder is endometriosis,polycystic ovarian disease, uterine fibroids, primary hirsutism,luteinizing hormone surge, or precocious puberty.

In another embodiment, the invention provides the use of a compound orpharmaceutically acceptable salt of the compound of Formula (I) orFormula (II) in the manufacture of a medicament for preventing pregnancyin a female mammal. In another embodiment, the compound orpharmaceutically acceptable salt of the compound is of the Formula (IA),(IB), (IC), or (ID).

In yet another embodiment, the uses of the compounds or pharmaceuticallyacceptable salts of compounds of the present invention further comprisethe use of a therapeutic agent selected from the group consisting ofandrogen, estrogen, progesterone, antiestrogen, antiprogestogen,testosterone, angiotensin-converting enzyme inhibitor, angiotensinII-receptor antagonist, renin inhibitor, bisphosphonate, growth hormonesecretagogue, 5a-reductase 2 inhibitor, a 5a-reductase 1 inhibitor, adual inhibitor of 5a-reductase 1 and 5a-reductase 2, antiandrogen,alpha-1 blockers, growth hormone, and luteinizing hormone releasingcompound; or a combination thereof in the manufacture of the medicamentsof the present invention.

In one embodiment, the present invention is directed to the use of acompound or pharmaceutically acceptable salt of the compound of Formula(I) or Formula (II) for the manufacture of a medicament for modulatingthe activity of a Gonadotropin Releasing Hormone receptor. In oneembodiment, the medicament is also for determining the activity of thereceptor. In another embodiment, the compound or pharmaceuticallyacceptable salt of the compound is of the Formula (IA), (IB), (IC), or(ID).

EXAMPLES

General Methods:

The following HPLC and LC/MS methods were used for the synthesesoutlined in the Examples.

Method A: Column: Xterra MS C18, 5 μ, 50×2.1 mm. Mobile phase:90/10-5/95 water (0.1% formic acid)/acetonitrile (0.1% formic acid), 2minutes, hold 1.5 minutes. Flow rate: 0.8 mL/min. Detection: 210-400 nm.

Method B: Column: Xterra reverse phase 18, 3.5 μ, 150×4.6 mm. Mobilephase: 85/15 to 5/95 ammonium formate buffer (pH=3.5)/acetonitrile andmethanol (1:1) for 10 minutes, hold 4 minutes. Flow rate: 1.2 mL/min.Detection: 210-370 nm.

Method C: YMC CombiPrep ProC18 50×20 mm I.D. column, S-5 μm, 12 nm. Flowrate 20 mL/minute. Gradient: 10/90 Acetonitrile/Water (0.1 % TFA in bothsolvents) to 100% acetonitrile over 10 minutes then hold for threeminutes at 100% acetonitrile and ramp back to 10/90 acetonitrile/waterover two minutes.

Example 1

6-Bromo-quinoxaline: In a round bottom flask under nitrogen was combined4-bromo-benzene-1,2-diamine (2.01 g, 10.7 mmol), methanol (50 mL), andglyoxal (40% by wt. 3.1 mL, 26.9 mmol) and the resulting solutionstirred overnight. The reaction was then concentrated in vacuo andpurified by flash column chromatography on silica gel using 5-10% ethylacetate in dichloromethane as eluant to yield 1.14 g (50% yield) of6-Bromo-quinoxaline as a yellow-orange solid. ¹H NMR (DMSO-d₆): 9.00(d,2H,J=2.8 Hz), 8.36 (d,1H,J=2.2 Hz), 8.07 (d,1H,J=9.0 Hz), 8.02(dd,1H,J=8.8,2.1 Hz). CHN for C₈H₅BrN₂: calc. C 45.97, H 2.41, N 13.4;found C 45.99, H 2.09, N 13.09. LC/MS (Method A): r.t.=1.10 min.,purity=99%, calculated mass=208, [M+H]⁺=209/211. HPLC (Method B):r.t.=7.4 min., purity=98.52% at 210-370 and 98.8% at 322 nm.

Example 2

6-Vinyl-quinoxaline: A mixture of 6-Bromo-quinoxaline (1.05 g, 5.02mmol), palladium tetrakistriphenylphosphine (0.232 g, 0.2 mmol), andlithium chloride (0.639 g, 15.1 mmol) in dry toluene (50 mL) undernitrogen was treated with tributylvinyl tin (4.4 mL, 15.1 mmol) andheated to 100° C. for three hours. After cooling to room temperature themixture was partitioned between ethyl acetate (200 mL) and water (100mL). The aqueous layer was discarded and the organics washed with brine(2×100 mL), dried with magnesium sulfate, filtered, and concentrated todryness on a rotary evaporator. Purification by flash columnchromatography on silica gel using 10% ethyl acetate in dichloromethaneas eluant yielded 680 mg (87% yield) of 6-Vinyl-quinoxaline as a lightorange solid. ¹H NMR (DMSO-d₆): 8.92 (dd,2H,J=14.1,1.9 Hz), 8.10 (m,3H),7.03 (dd,1H,J=17.7,10.9 Hz), 6.15 (dd,1H,J=17.7,0.4 Hz), 5.52(d,1H,J=11.1 Hz). LC/MS (Method A): r.t.=1.14 min., purity=99%,calculated mass=156, [M+H]⁺=157.

Example 3

Quinoxaline-6-carbaldehyde: To a mixture of 6-Vinyl-quinoxaline (0.68 g,4.35 mmol) in dioxane (44 mL) and water (35 mL) was added osmiumtetraoxide (2.5% wt in t-BuOH, 2.18 mL, 0.17 mmol) followed by sodiumperiodate (2.79 g, 13.1 mmol) and the reaction stirred for 3 h. Thesolution was diluted with ethyl acetate (150 mL) and then washed withwater (3×75 mL) followed by brine (75 mL). The organics were dried withmagnesium sulfate, filtered, and concentrated in vacuo. Purification byflash column chromatography on silica gel using 10-20% ethyl acetate indichloromethane as eluant yielded 470 mg (68% yield) ofQuinoxaline-6-carbaldehyde as a white solid. ¹H NMR (DMSO-d₆): 10.30(s,1H), 9.11 (d,2H,J=1.9 Hz), 8.74 (d,1H,J=1.4 Hz), 8.26 (m,2H). LC/MS(Method A): r.t.=0.69 min., purity=94.8%, calculated mass=158,[M+H]+=159.

Example 4

1-Ethyl-5-methyl-1H-imidazole-4-carbaldehyde:5-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved inTHF (40 mL) with DMF (5 mL). NaH (380 mg of a 60% dispersion in mineraloil) was added carefully and the reaction mixture was allowed to stirfor 5 min. under nitrogen. Ethyl iodide (1.65 g, 9.7 mmol) was added andit was allowed to stir for 1 h. The solvent was removed in vacuo, andthe crude was purified on silica eluted with 100% ethyl acetate—1%MeOH/ethyl acetate to yield the title product (390 mg) as the mainisomer. MS (ESI-POS): [M+H]⁺=139.

Example 5

1-Ethyl-5-methyl-1H-imidazole-4-carbaldehyde:5-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved inTHF (40 mL) with DMF (5 mL). NaH (380 mg of a 60% dispersion in mineraloil) was added carefully and the reaction mixture was allowed to stirfor 5 min. under nitrogen. Ethyl iodide (1.65 g, 9.7 mmol) was added andit was allowed to stir for 1 h, at which time the reaction was judgedcomplete. The solvent was removed under vacuum, and the crude waspurified on silica eluted with 100% ethyl acetate—1%MeOH/ethyl acetateto yield the title product (390 mg) as the main isomer. MS (ESI-POS):[M+H]⁺=139.

Example 6

1-Ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbaldehyde: Asuspension of 5-formyluracil (0.84 g, 6.0 mmol) in anhydrousdimethylformamide (12 mL) under a nitrogen atmosphere was cooled to −40°C. The reaction mixture was treated with sodium hydride (60% mineral oildispersion, 0.26 g, 6.6 mmol), stirred 30 min., then treated withiodoethane (0.53 mL, 6.6 mmol). The mixture warmed to 20° C. over 3 h.,then was brought to 40° C. for 48 h. At this time the reaction mixturewas cooled to room temperature, treated with methanol (5 mL) andevaporated to dryness under reduced pressure. The residue was purifiedby chromatography on silica gel eluted with a gradient of ethyl acetatein hexanes (1:3 to 1:2 to 1:1) to leave the product (0.25 g) as a whitepowder. MS (ESI-POS): [M+H]⁺=169.

Example 7

3-Methyl-pyrido[2,3-b]pyrazine: Pyridine-2,3-diamine (2.50 g, 22.9 mmol)was stirred in methanol (100 mL) and cooled in an ice bath and pyruvicaldehyde (40% wt., 4.20 mL, 27.5 mmol) was added, dropwise, and thesolution was allowed to warm to room temperature and stirred, undernitrogen for 18 h. The solvent was removed in vacuo to provide a blackoil (4.23 g). This material was adsorbed onto silica gel and purified bycolumn chromatography, eluting with a solution of 95:5chloroform:acetone to afford a dark red solid (2.96 g, 89% yield). HPLC(Method B): r.t.=3.2 min., purity 99.2% purity at 210-370 nm, 99.8% at238 nm, Calculated mass=145.06, [M+H]⁺=146.

Example 8

Pyrido[2,3-b]pyrazine-3-carbaldehyde: 3-Methyl-pyrido[2,3-b]pyrazine(1.00 g, 6.89 mmol) and selenium dioxane (800 mg, 7.2 mmol) were heatedto reflux in 1,4-dioxane (70 mL) and distilled water (2 mL), undernitrogen, for 4 h. The reaction mixture was cooled to room temperature,allowed to stand for 16 h, filtered through diatomaceous earth, washedwith ethyl acetate (50 mL) and the filtrate concentrated under reducedpressure. The residue was treated with dichloromethane (75 mL) andstirred for 30 min. The dichloromethane-soluble portion was added to acolumn of silica gel and eluted with ethyl acetate to leave the productaldehyde as a light brown solid (254 mg). LC/MS (Method A): r.t.=0.37min., purity=97.8%, calculated mass=159, [M+H]⁺=160.

Example 9

Quinoxaline-2-carbaldehyde: 2-Methyl-quinoxaline (1.00 mL, 7.75 mmol)and selenium dioxane (946 mg, 8.53 mmol) were heated to 90° C. (oil bathtemperature) in 1,4-dioxane (6 mL) and distilled water (4 mL), undernitrogen, for 18 h. The solvent was removed, in vacuo, and the materialdissolved in ethyl acetate (100 mL) and solid selenium precipitateformed and was filtered out of solution. The organic phase was washedwith saturated sodium bicarbonate solution (3×100 mL). The bicarbonatewashings were combined and extracted with ethyl acetate (2×100 mL). Theorganic extracts were combined and washed with brine (150 mL), dried(MgSO₄), filtered and the solvent removed in vacuo to give a red solid(440 mg). This material was adsorbed onto silica gel and purified bycolumn chromatography, eluting with a solution of 4:1 hexane:ethylacetate to afford a tan solid (180 mg, 15% Yield). ¹H NMR 300 MHz(DMSO): δ=□0.20 (s, 1H), 9.40 (s, 1H), 8.35 (dd, 1H, J=7.9 Hz, J=1.5Hz), 8.25 (dd, 1H, J=7.7 Hz, J=1.1 Hz), 8.08 (m, 2H).

Example 10

6-Methyl-quinoxaline: A solution of 4-methyl-1,2-phenylenediamine (5.0g, 41 mmol) in methanol (250 mL) was treated with a solution of 40%aqueous glyoxal and stirred for 16 h. The solvent was evaporated and theresidue was distilled under vacuum (2 mm Hg, 85-88° C.) to leave acolorless oil (1.5 g, 25%). LC/MS (Method A): r.t.=1.02 min.,purity=99.5%.

Example 11

6-Bromomethyl-quinoxaline: A mixture of 6-methylquinoxaline (1.5 g, 10.4mmol), N-bromosuccinimide (2.2 g, 12.5 mmol) and benzoylperoxide (0.30g, 1.25 mmol) in benzene (35 mL) was stirred rapidly and heated toreflux for 5 h. Upon cooling, the mixture was diluted with ethyl acetate(25 mL), washed with IN sodium hydroxide solution (50 mL) and saturatedsodium chloride solution (50 mL). The organic layer was dried (MgSO₄)and evaporated to a crystalline solid (2.5 g, 77% desired product, 23%α,α-dibrominated product as determined by ¹H NMR). The mixture was usedin subsequent reactions.

Example 12

8-Bromo-2-(4-tert-butyl-phenyl)-imidazo[1,2-a]pyridine:2-Amino-3-bromopyridine (0.250 g, 1.45 mmol) and 4-tert-butylphenacylchloride (0.306 g, 1.45 mmol) were dissolved in isopropanol (4.5 mL) andtreated with sodium bicarbonate (0.146 g, 1.74 mmol). The mixture wasstirred in a sealed tube at 80° C. for 48 h. The mixture wasconcentrated under reduced pressure and redissolved in ethyl acetate (30mL). The organic mixture was washed with water and saturated sodiumchloride, dried over magnesium sulfate, filtered and concentrated underreduced pressure. The crude material was purified by flash silica gelchromatography, eluting with 10% acetone/hexane to give 0.370 g (77%) ofthe title compound. HPLC (Method B): r.t.=10.7 min., purity 100% at210-370 nm, 99.3% at 252 nm. HRMS: calcd for C₁₇H₁₇BrN₂+H⁺, 329.06478;found (ESI, [M+H]+), 329.0662.

Example 13

2-(4-tert-Butyl-phenyl)-8-chloro-imidazo[1,2-a]pyridine: Using2-amino-3-chloropyridine prepared by a known method (Org. Lett.,5:1369-1372 (2003)) in place of 2-amino-3-bromopyridine,2-(4-tert-butyl-phenyl)-8-chloro-imidazo[1,2-a]pyridine was preparedfollowing the procedure outlined in Example 12. The crude material waspurified by flash silica gel chromatography, eluting with 1%methanol/dichloromethane (R_(f)=0.65) to give (44.5%) of the titlecompound. MS (ESI) m/z 285; HPLC (Method B): r.t.=10.6 min., purity99.1% at 210-370 nm, 98.5% at 250 nm. HRMS: calcd for C₁₇H₁₇C1N₂+H⁺,285.11530; found (ESI, [M+H]⁺), 285.1135.

Example 14

2-(4-tert-Butyl-phenyl)-8-piperazin-1-yl-imidazo[1,2-a]pyridine: To aflask containing 8-bromo-2-(4-tert-butyl-phenyl)-imidazo[1,2-a]pyridine(0.313 g, 0.951 mmol) was added tris(dibenzylidineacetone)dipalladium(0)(0.087 g, 0.0.0951 mmol), 2-(di-tert-butylphosphino)biphenyl (0.028 g,0.0951 mmol), sodium tert-butoxide (0.183 g, 1.90 mmol) and piperazine(0.409 g, 4.76 mmol). The solid reagents were then suspended in degassedtoluene (22 mL). The mixture was purged with nitrogen and heated to 115°C. for 2 h. The reaction mixture was concentrated to dryness underreduced pressure. The crude mixture was purified by flash silica gelchromatography, eluting with 15% methanol/chloroform to give 0.242 g(76%) of the title compound. MS (ES) m/z 335.1; HPLC (Method B):r.t.=8.4 min., purity 98.6% at 210-370 nm. HRMS: calcd for C₂₁H₂₆N₄+H⁺,335.22302; found (ESI, M+H), 335.2236.

Example 15

4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazine-1-carboxylicacid benzyl ester: To a flask containing the aryl chloride2-(4-tert-Butyl-phenyl)-8-chloro-imidazo[1,2-a]pyridine (0.140 g, 0.49mmol) was added palladium(II) acetate (0.010 g, 0.04 mmol),2-(di-tert-butylphosphino)biphenyl (0.020 g, 0.07 mmol), sodiumtert-butoxide (0.067 g, 0.70 mmol) and Cbz-piperazine (9.6 mL, 50 mmol).The mixture was purged with nitrogen and heated to 100° C. for 24 h in asealed tube. The reaction was about 50% complete at 24 h by LC/MSmonitoring, so an additional amount (equivalent to original amount) ofcatalyst, ligand, and base was added and heating was resumed for another3 h. The reaction mixture was cooled to room temperature and dilutedwith ethyl acetate (100 mL), which was washed with water and brine. Theethyl acetate was dried with MgSO₄ and concentrated. The crude mixturewas purified by flash silica gel chromatography, eluting with 25% ethylacetate/hexane (R_(f)=0.4) to give 0.16 g (70%) of the title compound.MS (ESI) m/z 469; HPLC (Method B): r.t.=11.8 min., purity 94.7% at210-370 nm, 98.0% at 240 nm. HRMS: calcd for C₂₉H₃₂N₄O₂+H⁺, 469.25980;found (ESI, [M+H]⁺), 469.2582.

The Cbz-protecting group was removed by catalytic hydrogenation to give2-(4-tert-Butyl-phenyl)-8-piperazin-1-yl-imidazo[1,2-a]pyridine in 82.3%yield.

Example 16

2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridine: A solution of2-aminopyridine (0.512 g, 5.44 mmol) and 4-tert-butylphenacyl chloride(1.26 g, 5.98 mmol) in isopropanol (16 mL) was treated with sodiumbicarbonate (0.914 g, 10.9 mmol) and heated in a sealed tube at 80° C.overnight. The mixture was concentrated under reduced pressure,re-dissolved in ethyl acetate (200 mL) and washed with water (2×100 mL)and saturated sodium chloride (100 mL). The organic layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by flash silica gel chromatography, elutingwith 20% acetone/hexanes to yield 0.841 g (62%) of the purified product.MS (ESI) m/z 251.1528; HPLC (Method B): r.t.=8.4 min., purity 100% at210-370 nm, 100% at 306 nm. HRMS: calcd for C₁₇H₁₈N₂+H⁺, 251.15427;found (ESI, [M+H]⁺), 251.1528.

Example 17

5-Bromo-2-(4-tert-butyl-phenyl)-imidazo[1,2-a]pyridine: A solution of2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridine (0.626 g, 2.50 mmol) inTHF (17 mL) was cooled to −78° C. The solution was treated withn-butyllithium (1.72 mL of 1.6 M solution in hexanes, 2.75 mmol)dropwise. The solution was stirred at −78° C. for 30 minutes, and thentreated dropwise with a solution of 1,2-dibromotetrafluoroethane (0.715g, 2.75 mmol) in THF (2 mL). Stirring at −78° C. was continued for 5minutes, and the reaction was warmed to room temperature over 20minutes. After quenching with water (50 mL), the mixture was extractedwith ethyl acetate (100 mL). The organic layer was washed with saturatedsodium chloride (25 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure. Unreacted starting material wasremoved from the crude product mixture by flash silica gelchromatography, eluting with 20% acetone/hexanes to furnish a 76% yield(0.281 g as mixture of three isomeric bromides) based on recoveredstarting material. The mixture was separated by preparative HPLC forisomer characterization. Alternatively, the mixture could be useddirectly in the next step.

Major Isomer (a); 5-bromo-2-(4-tert-butylphenyl)imidazo[1,2-a]pyridine:MS (ESI) m/z 329.0642; HPLC (Method B): r.t.=11.1 min., purity 100% at210-370 mn, 100% at 252 nm. HRMS: calcd for C₁₇H₁₇BrN₂+H⁺, 329.06478;found (ESI, [M+H]+), 329.0642.

Minor Isomer (b); 8-bromo-2-(4-tert-butylphenyl)imidazo[1,2-a]pyridine:HPLC (Method B): r.t.=10.7 min., purity 100% at 210-370 nm, 99.3% at 252nm. HRMS: calcd for C₁₇H₁₇BrN₂+H⁺, 329.06478; found (ESI, [M+H]⁺),329.0662.

Minor Isomer (c); 3-bromo-2-(4-tert-butylphenyl)imidazo[1,2-a]pyridine:MS (ESI) m/z 329.0639; HPLC (Method B): r.t.=11.1 min., purity 96.3% at210-370 nm, 96.8% at 248 nm. HRMS: calcd for C₁₇H₁₇BrN₂+H⁺, 329.06478;found (ESI, [M+H]⁺), 329.0639.

Example 18

2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine: Themixture of isomeric bromides prepared in Example 17 (0.054 g, 0.165mmol) was dissolved in DMSO (3.5 mL) and treated with piperazine (0.568g, 6.60 mmol). The mixture was shaken at 160° C. overnight. The mixturewas diluted with ethyl acetate (20 mL) and washed with 10% HCl (2×20mL). The aqueous layers were separated, basified with saturated sodiumcarbonate and re-extracted with ethyl acetate (3×20 mL). The organicsolution was dried over magnesium sulfate, filtered and concentratedunder reduced pressure to yield 0.051 g of crude material. The crudematerial could be purified by semi-preparative RP-HPLC (Method C). Thepurified fractions were combined and concentrated under reduced pressureto remove acetonitrile. The aqueous residue was basified with saturatedsodium carbonate and extracted with ethyl acetate (3×15 mL). The organicextracts were dried over magnesium sulfate, filtered and concentratedunder reduced pressure to yield 13 mg (25%) of the title compound.Alternatively, the crude material could be used directly in the nextstep. HPLC (Method B): r.t.=6.2 min., purity 100% at 210-370 nm, 97.4%at 250 nm. HRMS: calcd for C₂₁H₂₆N₄+H⁺, 335.22302; found (ESI, [M+H]⁺),335.2228.

Example 19

2-(4-tert-Butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine: 2-Aminopyridinewas converted to 1,2-diaminopyridinium iodide from a known literaturemethod (J. Org. Chem., 31:260-265 (1996)). 1,2-Diaminopyridinium iodide(0.270 g, 1.1 mmol) was treated with 4-tert-butyl-benzoyl chloride(0.432 g, 2.2 mmol) in pyridine (2 mL). The reaction was heated at 85°C. in a sealed tube for 3 h, at which time the mixture was cooled toroom temperature. The reaction was partitioned between ethyl acetate (50mL) and water (50 mL). The ethyl acetate extract was dried overmagnesium sulfate and concentrated. The crude material was purified byflash silica gel chromatography, eluting with 25% ethyl acetate/hexanes(R_(f)=0.4) to yield 0.205 g (74%) of the purified product. MS (ES) m/z252.2; HPLC (Method B): r.t.=6.7 min., purity 100% at 210-370 nm, 100%at 254 nm. HRMS: calcd for C₁₆H₁₇N₃+H⁺, 252.14952; found (ESI, [M+H]³⁰), 252.149.

Example 20

2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyridine:The lithiation and bromination procedure was performed according to aknown literature method (J. Org. Chem., 57:5538-5540 (1992)). To2-(4-tert-butylphenyl)[1,2,4]triazolo[1,5-a]pyridine (125 mg, 0.5 mmol)in THF (3 mL) at −78° C. was added n-butyllithium (220 μL of 2.5 Msolution in hexanes, 0.55 mmol). The reaction was stirred for 30 min at−78° C. and then treated dropwise with a solution of1,2-dibromotetrafluoroethane (66 μL, 0.55 mmol). Stirring at −78° C. wascontinued for 5 minutes, and the reaction was warmed to room temperatureover 20 minutes. After quenching with water (5 mL), the mixture wasextracted with ethyl acetate (40 mL). The organic layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Thecrude material was purified by flash silica gel chromatography, elutingwith 25% ethyl acetate/hexanes to yield 20 mg (12.1%) of the purifiedproduct, 5-Bromo-2-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine(I13369-101). LC/MS (Method A): r.t.=2.0 min. purity 97.4%, calculatedmass=330 [M+H]⁺=330 and 332.

5-Bromo-2-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (20 mg,60 μM) and piperazine (21 mg, 244 μM) in DMSO was heated at 80° C. for 8h. The reaction was cooled and diluted with ethyl acetate (25 mL) andwater (25 mL). After partitioning the ethyl acetate layer was washedwith water (3×) and dried over magnesium sulfate. After filtering andconcentration the title compound was obtained in 80% yield. LC/MS(Method A): r.t.=1.26 min. calculated mass=335 [M+H]⁺=336.

Example 21

6-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline:2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (0.086g, 0.258 mmol) was dissolved in DMSO (1 mL) and treated with6-bromomethyl-quinoxaline (0.072 g, 0.323 mmol) followed bydiisopropylethylamine (0.046 mL, 0.258 mmol). The mixture was stirred atroom temperature overnight and diluted with ethyl acetate (10 mL). Thesolution was washed with water and saturated sodium chloride, dried overmagnesium sulfate, filtered and concentrated under reduced pressure toyield the crude product. Purification by flash silica gel chromatography(40-50% acetone/hexanes) gave 0.0362 g (29%) of the title compound. HPLC(Method B): r.t.=9.6 min., purity 100% at 210-370 nm, 96.0% at 238 nm.HRMS: calcd for C₃₀H₃₂N₆+H⁺, 477.27612; found (ESI, [M+H]⁺), 477.2786.

Example 22

3-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-pyrido[2,3-b]pyrazine:Crude 2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine(0.100 g, 0.298 mmol) and pyrido[2,3-b]pyrazine-3-carbaldehyde (0.062 g,0.378 mmol) was dissolved in NMP (5 mL). The mixture was treated with 3drops of glacial acetic acid, followed by sodium triacetoxyborohydride(0.126 g, 0.596 mmol.) The mixture was stirred at room temperatureovernight and then purified by semipreparative RP-HPLC (Method C)followed by basification as in example 18 to obtain 0.0155 g of thetitle compound (11%). HPLC (Method B): r.t.=9.0 min., purity 85.2% at210-370 nm, 81.1% at 252 nm. HRMS: calcd for C₂₉H₃₁N₇+H⁺, 478.27137;found (ESI, [M+H]⁺), 478.271.

Example 23

2-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline:Prepared as described in Example 22, but usingquinoxaline-2-carbaldehyde in place ofpyrido[2,3-b]pyrazine-3-carbaldehyde. HPLC (Method B): r.t.=10.5 min.,purity 100% at 210-370 nm, 96.9% at 238 nm. HRMS: calcd for C₃₀H₃₂N₆+H⁺,477.27612; found (ESI, [M+H]⁺), 477.2762.

Example 24

2-(4-tert-Butyl-phenyl)-5-[4-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine:Prepared as in Example 22, but using2-ethyl-5-methyl-1H-imidazole-4-carbaldehyde with 1,2-dichlorethane asthe solvent, which was removed under reduced pressure prior topurification as described for example 18. MS (ES) m/z 455.2; HPLC(Method B): r.t.=7.6 min., purity 100% at 210-370 nm, 99.3% at 252 nm.HRMS: calcd for C₂₈H₃₆N₆+H⁺, 457.30742; found (ESI, [M+H]⁺), 457.3081.

Example 25

5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione:Prepared following the procedure of Example 22 using as the aldehyde1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde withdichloromethane as the solvent, which was removed under reduced pressureprior to purification as described for example 18. HPLC (Method B):r.t.=7.1 min., purity 82.1% at 210-370 nm, 81.3% at 252 nm. HRMS: calcdfor C₂₈H₃₄N₆O₂+H⁺, 487.28160; found (ESI, [M+H]⁺), 487.2806.

Example 26

5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione:Prepared following the procedure of Example 22 using as the aldehyde5-formyluracil with dichloromethane as the solvent, which was removedunder reduced pressure prior to purification as described for example18. HPLC (Method B): r.t.=6.5 min., purity 90.1% at 210-370 nm, 90.5% at252 nm. HRMS: calcd for C₂₆H₃₀N₆O₂+H⁺, 459.25030; found (ESI, [M+H]⁺),459.2493.

Example 27

5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione:The piperazine derivative2-(4-tert-Butyl-phenyl)-8-piperazin-1-yl-imidazo[1,2-a]pyridine (0.101g, 0.302 mmol) and 5-formyluracil (0.055 g, 0.393 mmol) were dissolvedin DMF (4 mL) and treated with 3 drops of glacial acetic acid and sodiumtriacetoxyborohydride (0.128 g, 0.604 mmol.) The mixture was stirred atroom temperature overnight and then purified by semipreparative RP-HPLC(Method C) followed by basification as in example 18 to give 0.0235 g(17%) of the title compound. MS (ESI) m/z 459; MS (ESI) m/z 457; HPLC(Method B): r.t.=8.0 min., purity 74.1% at 210-370 nm, 75.0% at 260 nm.HRMS: calcd for C₂₆H₃₀N₆O₂+H⁺, 459.25030; found (ESI-FTMS, [M+H]⁺),459.25175.

Example 28

5-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione:Prepared as in Example 27, but using the aldehyde1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde. MS (ES)m/z 485.2; HPLC (Method B): r.t.=8.4 min., purity 87.4% at 210-370 nm,86.7% at 300 nm. HRMS: calcd for C₂₈H₃₄N₆O₂+H⁺, 487.28160; found (ESI,[M+H]⁺), 487.2829.

Example 29

2-(4-tert-Butyl-phenyl)-8-[4-(2-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine:Prepared as in Example 27, but using the aldehyde2-ethyl-5-methyl-1H-imidazole-4-carbaldehyde in 1,2-dichloroethane asthe solvent, which was removed under reduced pressure prior topurification. MS (ES) m/z 457.2; HPLC (Method B): r.t.=8.7 min., purity93.1% at 210-370 nm, 91.8% at 262 nm. HRMS: calcd for C₂₈H₃₆N₆+H⁺,457.30742; found (ESI, [M+H]⁺), 457.3093.

Example 30

2-(4-tert-Butyl-phenyl)-8-[4-(1-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]-imidazo[1,2-a]pyridine:Prepared following the procedure of Example 27, using the aldehyde1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde in 1,2-dichloroethane asthe solvent, which was removed under reduced pressure prior topurification. MS (ESI) m/z 457; HPLC (Method B): r.t.=9.0 min., purity100% at 210-370 nm, 99.5% at 260 nm. HRMS: calcd for C₂₈H₃₆N₆+H⁺,457.30742; found (ESI, [M+H]⁺), 457.3052.

Example 31

6-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline:Prepared following the procedure of Example 27, using the aldehydequinoxaline-6-carbaldehyde in NMP as the solvent. The crude material waspurified by semi-preparative RP-HPLC (Method C) without the use of TFAbuffer. Purified product was lyophilized and gave the title compound in44.2% yield. HPLC (Method B): r.t.=9.6 min., purity 100% at 210-370 nm,100% at 260 nm. HRMS: calcd for C₃₀H₃₂N₆+H⁺, 477.27612; found (ESI,[M+H]⁺), 477.2746.

Example 32

2-{4-[2-(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline:Prepared following the procedure of Example 27, using the aldehydequinoxaline-2-carbaldehyde in NMP as the solvent. The crude material waspurified by semi-preparative RP-HPLC (Method C) without the use of TFAbuffer. Purified product was lyophilized and gave the title compound in50% yield. HPLC (Method B): r.t.=10.9 min., purity 100% at 210-370 nm,100% at 264 nm. HRMS: calcd for C₃₀H₃₂N₆+H⁺, 477.27612; found (ESI,[M+H]⁺), 477.278.

Example 33

2-{4-[2-(4-tert-Butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline:Prepared using according to the procedure outlined in Example 32 using2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyridine.Workup consisted of partitioning the reaction mixture between ethylacetate (50 mL) and saturated sodium bicarbonate (50 mL). The organiclayer was washed with water (3×50 mL), dried over magnesium sulfate,filtered and concentrated under reduced pressure. The crude material waspurified by flash silica gel chromatography, eluting with 50% ethylacetate/hexanes (R_(f)=0.20) to yield the purified product in 26% yield.MS (ES) m/z 478.4; HPLC (Method B): r.t.=11.3 min., purity 100% at210-370 nm, 99.4% at 266 nm. HRMS: calcd for C₂₉H₃₁N₇+H⁺, 478.27137;found (ESI, [M+H]⁺), 478.2723.

Example 34

Biological Evaluation

COS cell membranes containing human GnRH receptors were incubated withradioactively labeled D-trp6 GnRH in the presence of increasingconcentrations of test compound. Membrane bound radioactivity wasmeasured after separating the free radioactivity by filtration method,and IC₅₀ values were calculated using SAS analysis system. (See,“Receptor-binding Affinity of Gonadotropin-releasing Hormone Analogs:Analysis by Radioligand-receptor assay” Endocrinology, 106:1154-1159(1980)).

All compounds tested had hGnRH binding IC₅₀'s between 1 and 1000 nm.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein X is N or C—R₂₈;Y is Q and Z is R₁₈; or Y is R₁₈ and Z is Q, wherein Q is

Ar is phenyl, 2-thiophenyl or 3-thiophenyl; R₁ and R₂ are eachindependently hydrogen; or linear or branched (C₁—C₆)-alkyl,(C₂—C₆)-alkenyl, or (C₂—C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;or R₁ and R₂ may together form a three- to seven-membered cycloalkylgroup, wherein the cycloalkyl group formed by R₁ and R₂ is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃; R₃ is one of thefollowing:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, and R₂₈ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃; R₇ and R₉ areeach independently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇;—COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—R₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃;R₁₅ and R₁₆ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆may together form a three- to seven-membered heterocyclic groupcontaining up to 3 heteroatoms selected from N, O, or S; R₁₇ is phenyl,2-pyridyl, 3-pyridyl, or 4-pyridyl; R₁₈, R₁₉, and R₂₀ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;halogen; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃;—CO₂R₁₃; or —CON(R₁₃)(R₁₄); X₁ is —O-, —NR₁₂-, or —SO_(m)—; each m isindependently 0, 1, or 2; and each n is independently 0, 1, 2, 3, or 4.2. The compound of claim 1 of the formula (IA):

or a pharmaceutically acceptable salt thereof, wherein Ar, R_(1, R) ₂,R₃, R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ areas in claim
 1. 3. The compound of claim 1 of the formula (IB):

or a pharmaceutically acceptable salt thereof wherein Ar, R₁, R₂, R₃,R₄, R₅, R₆, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, R₂₇, and R₂₈ are asin claim
 1. 4. The compound or pharmaceutically acceptable salt of thecompound of claim 1, wherein Ar is phenyl.
 5. The compound orpharmaceutically acceptable salt of the compound of claim 4, wherein oneR₆ substituent is attached at the 4 position of phenyl.
 6. The compoundor pharmaceutically acceptable salt of the compound of claim 1, whereinR₁ is methyl and R₂ is hydrogen.
 7. The compound or pharmaceuticallyacceptable salt of the compound of claim 1, wherein R₄ is methyl orethyl and R₅ is hydrogen.
 8. The compound or pharmaceutically acceptablesalt of the compound of claim 1, wherein when R₄ is other than hydrogen,the compound or pharmaceutically acceptable salt of the compound is theS-enantiomer with respect to the carbon to which R₄ is bound.
 9. Thecompound or pharmaceutically acceptable salt of the compound of claim 5,wherein the one R₆ substituent is ethyl, t-butyl, —N(CH₂CH₃)₂,pyrrolidine, 2-hydroxymethylpyrrolidine, or isopropyl.
 10. The compoundor pharmaceutically acceptable salt of the compound of claim 1, whereinR₃ is


11. The compound or pharmaceutically acceptable salt of the compound ofclaim 1, wherein R₃ is


12. The compound or pharmaceutically acceptable salt of the compound ofclaim 1, wherein R₂, R₅, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇are each hydrogen; R₁ and R₄ are each independently hydrogen, methyl, orethyl; Ar is phenyl; one R₆ is attached at the 4-position of phenyl andis ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine, 2-hydroxymethylpyrrolidine,or isopropyl; and R₃is


13. The compound or pharmaceutically acceptable salt of the compound ofclaim 1, wherein the compound is6-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline; 3-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin -1-ylmethyl}- pyrido[2,3-b]pyrazine;2-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline; 2—(4-tert-Butyl-phenyl)-5-[4—(2-ethyl-5-methyl -1H-imidazol-4-ylmethyl)-piperazin -1-yl]- imidazo[1,2-a]pyridine;5-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione;5-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-5-yl]-piperazin-1-ylmethyl}-1 H- pyrimidine-2,4-dione;5-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1H-pyrimidine-2,4-dione;5-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-1-ethyl -1H-pyrimidine-2,4-dione; 2—(4-tert-Butyl-phenyl)-8-[4—(2-ethyl-5-methyl -1H-imidazol-4-ylmethyl)-piperazin-1yl]-imidazo[1,2-a]pyridine;2—(4-tert-Butyl-phenyl)-8-[4—(1-ethyl-5-methyl-1H-imidazol-4-ylmethyl)-piperazin-1-yl]- imidazo[1,2-a]pyridine;6-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline;2-{4-[2—(4-tert-Butyl-phenyl)-imidazo[1,2-a]pyridin-8-yl]-piperazin-1-ylmethyl}-quinoxaline;and2-{4-[2—(4-tert-Butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazin-1-ylmethyl}-quinoxaline.
 14. A compound of the formula (11):

or a pharmaceutically acceptable salt thereof, wherein Y is Q and Z ishydrogen; or Y is hydrogen and Z is Q, wherein Q is

R₁ and R₂ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a three-to seven-membered cycloalkyl group, wherein the cycloalkyl group formedby R₁ and R₂ is optionally substituted with halogen, —N₃, —NO₂, —CN,—OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃;R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, and R₂₃ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ is independently hydrogen;linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl,each optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; —NR₁₃R₁₄; —C(OH)(CF₃)₂;—CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and when the two R₆ are ortho toeach other, they may together form a five- to seven-membered cyclicgroup containing up to 3 heteroatoms selected from N, O, or S, andwherein the cyclic group formed by the ortho R₆ groups is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃; R₇ and R₉ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇;—COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₁₅ and R₁₆ areeach independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₇ is phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl; X₁ is —O-, —NR₁₂-, or —SO_(m)-; each m isindependently 0, 1, or 2; and each n is independently 0, 1, 2, 3, or 4.15. The compound or pharmaceutically acceptable salt of the compound ofclaim 14, wherein R₁ and R₄ are each independently hydrogen, methyl, orethyl; R₂ and R₅ are hydrogen; one R₆ is attached at the 4-position ofphenyl and is ethyl, t-butyl, —N(CH₂CH₃)₂, pyrrolidine,2-hydroxymethylpyrrolidine, or isopropyl; and R₃is


16. A composition comprising an effective amount of the compound or apharmaceutically acceptable salt of the compound of claim 1 and apharmaceutically acceptable carrier.
 17. The composition of claim 16,further comprising a therapeutic agent selected from the groupconsisting of androgen, estrogen, progesterone, antiestrogen,antiprogestogen, testosterone, angiotensin-converting enzyme inhibitor,angiotensin II-receptor antagonist, renin inhibitor, bisphosphonate,growth hormone secretagogue, 5a-reductase 2 inhibitor, a 5a-reductase 1inhibitor, a dual inhibitor of 5a-reductase 1 and 5a-reductase 2,antiandrogen, alpha-1 blockers, growth hormone, and luteinizing hormonereleasing compound; or a combination thereof.
 18. The composition ofclaim 16, wherein the pharmaceutically acceptable carrier is suitablefor oral administration and the composition comprises an oral dosageform.
 19. A method of synthesizing a compound comprising: a) reacting anaminopyridine of the formula (III):

wherein R₂₉ is Cl or Br, R₁₈, R₁₉, and R₂₀ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or—CON(R₁₃)(R₁₄); R₁₃ and R₁₄ are each independently hydrogen; linear orbranched (C₁-C₆)—alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂; aryl; or aryl optionally substituted with one to threesubstituents selected from halogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ andR₁₄ may together form a three- to seven-membered heterocyclic groupcontaining up to 3 hereroatoms selected from N, O, or S, and wherein theheterocyclic group formed by R₁₃ and R₁₄ is optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or—(CH₂)_(n)OR₂₃; R₁₅ and R₁₆ are each independently hydrogen; or linearor branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or bothR₁₅ and R₁₆ may together form a three- to seven-membered heterocyclicgroup containing up to 3 heteroatoms selected from N, O, or S; R₂₃ ishydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; X₁ is —O—, —NR₁₂—, or SO_(m) ⁻; R₁₂ is hydrogen; orlinear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;each m is independently 0, 1, or 2; each n is independently 0, 1, 2, 3,or 4; under conditions effective to bring about cyclization, therebyproviding a compound having the formula (IV):

wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃ ₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃; and R₂₈ ishydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; b) reacting the compound of formula (IV) with apiperazine, thereby providing a compound having the formula (V):

R₄, R₅, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are each independentlyhydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; c) reacting the free amine of the piperazine of formula(V) under conditions effective to provide a compound of the formula(IA):

wherein R₁ and R₂ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a three-to seven-membered cycloalkyl group, wherein the cycloalkyl group formedby R₁ and R₂ is optionally substituted with halogen, —N₃, —NO₂, —CN,—OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₇ and R₉ are each independently hydrogen;linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂; R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or—(CH₂)_(m)CONR₁₁R₁₂; and each R₁₀ is independently hydrogen; or linearor branched C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; R₁₁ ishydrogen; linear or branched C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form a three- toseven-membered heterocyclic group containing up to 3 heteroatomsselected from N, O, or S; and R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl.
 20. A method of synthesizing a compound comprising: a)reacting an aminopyridine of the formula (VI):

wherein R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;—C(OH)(CF₃)₂; —CH(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or —CONR(R₁₃)(R₁₄);R₁₃ and R₁₄ are each independently hydrogen; linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted withone to three substituents selected from halogen, R₁₅, —OR₁₅, or—NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to seven-memberedheterocyclic group containing up to 3 heteroatoms selected from N, O, orS, and wherein the heterocyclic group formed by R₁₃ and R₁₄ isoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃; R₁₅ and R₁₆are each independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₂₃ is hydrogen; or linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; X₁ is —O—,—NR₁₂—, or SO_(m) ⁻; R₁₂ is hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each m isindependently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4;under conditions effective to bring about cyclization, thereby providinga compound having the formula (VII):

wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃; R₂₈ ishydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; b) halogenating the compound of the formula (VII) andreacting with a piperazine, thereby providing a compound having theformula (VIII):

wherein R₄, R₅, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are each independentlyhydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; and c) reacting the free amine of the piperazine offormula (VIII) under conditions effective to provide a compound of theformula (IB):

wherein R₁ and R₂ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a three-to seven-membered cycloalkyl group, wherein the cycloalkyl group formedby R₁ and R₂ is optionally substituted with halogen, —N₃, —NO₂, —CN,—OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₇ and R₉ are each independently hydrogen;linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂; R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or—(CH₂)_(m)CONR₁₁R₁₂; each R₁₀ is independently hydrogen; or linear orbranched C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; R₁₁ ishydrogen; linear or branched C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form a three- toseven-membered heterocyclic group containing up to 3 heteroatomsselected from N, O, or S; and R₁₇ is phenyl, 2-pyridyl, 3-pyridyl, or4-pyridyl.
 21. A method of synthesizing a compound comprising: a)reacting an aminopyridine of the formula (VI):

wherein R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear orbranched (C 1-C₆)- alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;—C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or —CON(R,3)(R₁₄); R₁₃ and R₁₄ are each independently hydrogen; linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted withone to three substituents selected from halogen, R₁₅, —OR₁₅, or—NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to seven-memberedheterocyclic group containing up to 3 heteroatoms selected from N, O, orS, and wherein the heterocyclic group formed by R₁₃ and R₁₄ isoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₁₅ and R₁₆ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₂₃ is hydrogen; or linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; X₁ is —O-,—NR₁₂-, or —SO_(m); R₁₂ is hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each m isindependently 0, 1, or 2; each n is independently 0, 1, 2, 3, or 4;under conditions effective to provide a diaminopyridinium iodide havingthe formula (IX):

b) reacting the compound of the formula (IX) under conditions effectiveto bring about cyclization, thereby providing a compound having theformula (X):

wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R 14; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; andwhen the two R₆ are ortho to each other, they may together form a five-to seven-membered cyclic group containing up to 3 heteroatoms selectedfrom N, O, or S, and wherein the cyclic group formed by the ortho R₆groups is optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃,—SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or c) halogenating the compoundof the formula (X) and reacting with a piperazine, thereby providing acompound having the formula (XI):

wherein R₄, R₅, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are each independentlyhydrogen; or linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; and d) reacting the free amine of the piperazine offormula (XI) under conditions effective to provide a compound of theformula (IC):

wherein R, and R₂ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁ and R₂ may together form a three-to seven-membered cycloalkyl group, wherein the cycloalkyl group formedby R₁ and R₂ is optionally substituted with halogen, —N₃, —NO₂, —CN,—OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ is one of thefollowing:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₇ and R₉ are each independently hydrogen;linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂;R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; —(CH₂)_(m)CO₂R₁₁; or (CH₂)_(m)CONR₁₁R₁₂; each R₁₀ isindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; R₁₁ is hydrogen; linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ maytogether form a three- to seven-membered heterocyclic group containingup to 3 heteroatoms selected from N, O, or S; and R₁₇ is phenyl,2-pyridyl, 3-pyridyl, or 4-pyridyl.
 22. A method of synthesizing acompound comprising: a) reacting a hydrazinonitropyridine of the formula(XII):

wherein R₁₈, R₁₉, and R₂₀ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen; —NR₁₃R₁₄;—C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; orCON(R₁₃)(R₁₄); R₁₃ and R₁₄ are each independently hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —R₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryl optionally substituted withone to three substituents selected from halogen, R₁₅, —OR₁₅, or—NR₁₅R₁₆; or R₁₃ and R₁₄ may together form a three- to seven-memberedheterocyclic group containing up to 3 heteroatoms selected from N, O, orS, and wherein the heterocyclic group formed by R₁₃ and R₁₄ isoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(C H,)_(n)OR₂₃; R₁₅ and R₁₆are each independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₂₃ is hydrogen; or linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; X₁ is —O-,—NR₁₂-, or —SO_(m); R₁₂ is hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each m isindependently 0,1, or 2; each n is independently 0, 1, 2, 3, or 4; underconditions effective to provide a compound of the formula (XIII):

wherein Ar is phenyl, 2-thiophenyl or 3-thiophenyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or b) treating the compound offormula (XIII) under conditions effective to bring about isomerizationto provide a compound of the formula (XIV):

c) reducing the nitro group to provide a compound of the formula (XV):

d) diazotizing and halogenating the compound of formula (XV) andreacting with piperazine, thereby providing a compound of the formula(XVI):

wherein 1(4, 1(5, R₂₁, R₂₂, R₂₄, R₂₅, R₂₆, and R₂₇ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; and e) reacting the free amine ofthe piperazine of formula (XVI) under conditions effective to provide acompound of the formula (ID):

wherein R₁₁ and R₂ are each independently hydrogen; or linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, eachoptionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; or R₁₁ and R₂ may togetherform a three- to seven-membered cycloalkyl group, wherein the cycloalkylgroup formed by R₁ and R₂ is optionally substituted with halogen, —N₃,—NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃,—CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ isone of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₇ and R₉ are each independently hydrogen;linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇; —COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂;R₈ is hydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl; (CH₂)_(m)CO₂R₁₁; or (CH₂)_(m)CONR₁₁R₁₂; each R₁₀ isindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂—C₆)-alkenyl, or (C₂-C₆)-alkynyl; R₁₁ is hydrogen; linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ maytogether form a three- to seven-membered heterocyclic group containingup to 3 heteroatoms selected from N, O, or S; R₁₇ is phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl.
 23. A compound of the formula (IA):

prepared by a method comprising: a) reacting a compound of the formula(III):

under conditions effective to bring about cyclization, thereby providinga compound having the formula (IV):

b) reacting the compound of formula (IV) with a piperazine, therebyproviding a compound having the formula (V):

c) reacting the free amine of the piperazine of formula (V) underconditions effective to provide a compound of the formula (IA); whereinR₂₉ is Cl or Br; Ar is phenyl, 2-thiophenyl or 3-thiophenyl; R₁ and R₂are each independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;or R₁ and R₂ may together form a three- to seven-membered cycloalkylgroup, wherein the cycloalkyl group formed by R₁ and R₂ is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,R₂₇, and R₂₈ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₇ and R₉ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)XiR₁₂; —(CH₂)_(n)R₁₇;—COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(m)CO₂R₁₁; or —(CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—R₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₁₅ and R₁₆ areeach independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₇ is phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl; R₁₈, R₁₉, and R₂₀ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; orX₁ is —O-, —NR₁₂-, or —SO_(m); each m is independently 0,1, or 2; andeach n is independently 0, 1, 2, 3, or
 4. 24. A compound of the formula(IB):

prepared by a method comprising: a) reacting an aminopyridine of theformula (VI):

under conditions effective to bring about cyclization, thereby providinga compound having the formula (VII):

b) halogenating the compound of the formula (VII) and reacting with apiperazine, thereby providing a compound having the formula (VIII):

c) reacting the free amine of the piperazine of formula (VIII) underconditions effective to provide a compound of the formula (IB); whereinAr is phenyl, 2-thiophenyl or 3-thiophenyl; R₁ and R₂ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;or R₁ and R₂ may together form a three- to seven-membered cycloalkylgroup, wherein the cycloalkyl group formed by R₁ and R₂ is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,and R₂₇, and R₂₈ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃ COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃; R₇ and R₉ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X R₁₂; —(CH₂)_(n)R₁₇,—COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(m)CO₂R₁₁; or 4CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—R₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R_(n))₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or —(CH₂)_(n)OR₂₃;R₁₅ and R₁₆ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆may together form a three- to seven-membered heterocyclic groupcontaining up to 3 heteroatoms selected from N, O, or S; R₁₇ is phenyl,2-pyridyl, 3-pyridyl, or 4-pyridyl ; R₁₈, R₁₉, and R₂₀ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;halogen; —NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃;—CO₂R₁₃; or X₁ is —O-, —NR₁₂-, or —SO_(m); each m is independently 0, 1,or 2; and each n is independently 0, 1, 2, 3, or
 4. 25. A compound ofthe formula (IC):

prepared by a method comprising: a) reacting an aminopyridine of theformula (VI):

under conditions effective to provide a diaminopyridinium iodide havingthe formula (IX):

b) reacting the compound of the formula (IX) under conditions effectiveto bring about cyclization, thereby providing a compound having theformula (X):

c) halogenating the compound of the formula (X) and reacting with apiperazine, thereby providing a compound having the formula (XI):

d) reacting the free amine of the piperazine of formula (XI) underconditions effective to provide a compound of the formula (IC); whereinAr is phenyl, 2-thiophenyl or 3-thiophenyl; R₁ and R₂ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;or R₁ and R₂ may together form a three- to seven-membered cycloalkylgroup, wherein the cycloalkyl group formed by R₁ and R₂ is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,and R₂₇ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R₁₄—C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; and whenthe two R₆ are ortho to each other, they may together form a five- toseven-membered cyclic group containing up to 3 heteroatoms selected fromN, O, or S, and wherein the cyclic group formed by the ortho R₆ groupsis optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃,—SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃; R₇ and R₉ areeach independently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(GH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇;—COX₁R₁₁; —X₁R₁₁; —CO₂R₁₁; or —CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;—(CH₂)_(m)CO₂R₁₂; or —(CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—R₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₁₅ and R₁₆ areeach independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₇ is phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl; R₁₈, R₁₉, and R₂₀ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen;—NR₁₃R₁₄; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; orCON(R₁₃)(R 14); X₁ is —O-, —NR₁₂-, or —SO_(m); each m is independently0, 1, or 2; and each n is independently 0,1, 2, 3, or
 4. 26. A compoundof the formula (ID):

prepared by a method comprising: a) reacting a hydrazinonitropyridine ofthe formula (XII):

under conditions effective to provide a compound of the formula (XIII):

b) treating the compound of formula (XIII) under conditions effective tobring about isomerization to provide a compound of the formula (XIV):

c) reducing the nitro group to provide a compound of the formula (XV):

d) diazotizing and halogenating the compound of formula (XV) andreacting with piperazine, thereby providing a compound of the formula(XVI):

e) reacting the free amine of the piperazine of formula (XVI) underconditions effective to provide a compound of the formula (ID); whereinAr is phenyl, 2-thiophenyl or 3-thiophenyl; R₁ and R₂ are eachindependently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;or R₁ and R₂ may together form a three- to seven-membered cycloalkylgroup, wherein the cycloalkyl group formed by R₁ and R₂ is optionallysubstituted with halogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃,—SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃,—NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₃ is one of the following:

each R₃ also having up to three R₁₀ substituents attached to the ring ofR₃ containing at least one N; R₄, R₅, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆,and R₂₇ are each independently hydrogen; or linear or branched(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; each R₆ isindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl, each optionally substituted withhalogen, —N₃, —NO₂, —CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂,—COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂;—NR₁₃R 14; —C(OH)(CF₃)₂; —CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; or —COR₁₃; andwhen the two R₆ are ortho to each other, they may together form a five-to seven-membered cyclic group containing up to 3 heteroatoms selectedfrom N, O, or S, and wherein the cyclic group formed by the ortho R₆groups is optionally substituted with halogen, —N₃, —NO₂, —CN, —OR₂₃,—SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃, —NR₂₃CO₂R₂₃,—NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or (CH₂)_(n)OR₂₃; R₇ and R₉ areeach independently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; —(CH₂)_(n)X₁R₁₂; —(CH₂)_(n)R₁₇;—COX₁R_(n); —X₁R₁₁; —CO₂R₁₁; or—CONR₁₁R₁₂; R₈ is hydrogen; linear orbranched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl;(CH₂)_(m)CO₂R ; or (CH₂)_(m)CONR₁₁R₁₂; R₁₁ and R₁₂ are eachindependently hydrogen; linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or R₁₁ and R₁₂ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₃ and R₁₄ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—R₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; aryl; or aryloptionally substituted with one to three substituents selected fromhalogen, R₁₅, —OR₁₅, or —NR₁₅R₁₆; or R₁₃ and R₁₄ may together form athree- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S, and wherein the heterocyclic groupformed by R₁₃ and R₁₄ is optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, —CON(R₂₃)₂, or R₁₅ and R₁₆ areeach independently hydrogen; or linear or branched (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, or (C₂-C₆)-alkynyl; or both R₁₅ and R₁₆ may togetherform a three- to seven-membered heterocyclic group containing up to 3heteroatoms selected from N, O, or S; R₁₇ is phenyl, 2-pyridyl,3-pyridyl, or 4-pyridyl; R₁₈, R₁₉, and R₂₀ are each independentlyhydrogen; linear or branched (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, or(C₂-C₆)-alkynyl, each optionally substituted with halogen, —N₃, —NO₂,—CN, —OR₂₃, —SR₂₃, —SO₂R₂₃, —SO₂N(R₂₃)₂, —N(R₂₃)₂, —COR₂₃, —CO₂R₂₃,—NR₂₃CO₂R₂₃, —NR₂₃COR₂₃, —NR₂₃CON(R₂₃)₂, or —CON(R₂₃)₂; halogen;—NR₁₃R₁₄; —C(OH)(CF₃)₂; CH(CF₃)₂; —C(CF₃)₃; —X₁R₁₃; —COR₁₃; —CO₂R₁₃; or—CON(R₁₃)(R₁₄); X₁ is —O-, —NR₁₂-, or —SO_(m)-; each m is independently0, 1, or 2; and each n is independently 0, 1, 2, 3, or 4.